Rejection Surveillance After Heart Transplantation: Is Paired Noninvasive Testing the New Gold Standard?

Rejection surveillance after heart transplantation has traditionally relied on numerous endomyocardial biopsies, most of which occur during the first posttransplant year. With the introduction of gene expression profiling and, more recently, donor-derived cell-free DNA, a great proportion of surveillance is being performed noninvasively with both tests. Although patients have welcomed the use of paired testing because of the decreased risk and inconvenience, interpretation of both tests can sometimes be challenging, particularly when the test results are discordant. Growing evidence from both single-center experiences and large national databases has given insights that have allowed the field to operationalize dual testing and provide physicians with algorithms to approach paired testing. The increased use of noninvasive testing has also begun to challenge the role of biopsy as the gold standard for graft monitoring, not only for rejection but over the life of the heart transplant. In a growing number of circumstances, cell-free DNA not only may be a better means of assessing rejection but could also redefine how clinicians approach the diagnosis and even treatment of graft injury. As the heart transplant community garners more experience and generates more data, the current paradigms of heart transplant surveillance will continue to be challenged.

HLA sensitization is associated with an increased risk of primary graft dysfunction after heart transplantation.

Primary graft dysfunction (PGD) is a leading cause of early morbidity and mortality following heart transplantation (HT). We sought to determine the association between pretransplant human leukocyte antigen (HLA) sensitization, as measured using the calculated panel reactive antibody (cPRA) value, and the risk of PGD. METHODS: Consecutive adult HT recipients (n = 596) from 1/2015 to 12/2019 at 2 US centers were included. Severity of PGD was based on the 2014 International Society for Heart and Lung Transplantation consensus statement. For each recipient, unacceptable HLA antigens were obtained and locus-specific cPRA (cPRA-LS) and pre-HT donor-specific antibodies (DSA) were assessed. RESULTS: Univariable logistic modeling showed that peak cPRA-LS for all loci and HLA-A was associated with increased severity of PGD as an ordinal variable (all loci: OR 1.78, 95% CI: 1.01-1.14, p = 0.025, HLA-A: OR 1.14, 95% CI: 1.03-1.26, p = 0.011). Multivariable analysis showed peak cPRA-LS for HLA-A, recipient beta-blocker use, total ischemic time, donor age, prior cardiac surgery, and United Network for Organ Sharing status 1 or 2 were associated with increased severity of PGD. The presence of DSA to HLA-B was associated with trend toward increased risk of mild-to-moderate PGD (OR 2.56, 95% CI: 0.99-6.63, p = 0.053), but DSA to other HLA loci was not associated with PGD. CONCLUSIONS: Sensitization for all HLA loci, and specifically HLA-A, is associated with an increased severity of PGD. These factors should be included in pre-HT risk stratification to minimize the risk of PGD.

Cardiac MRI and Clinical Outcomes in TMEM43 Arrhythmogenic Cardiomyopathy.

Arrhythmogenic cardiomyopathy is an inherited cardiomyopathy that can involve both ventricles. Several genes have been identified as pathogenic in arrhythmogenic cardiomyopathy, including TMEM43. However, there are limited data on cardiac MRI findings in patients with TMEM43 variants to date. In this case series, cardiac MRI findings and clinical outcomes are described in 14 patients with TMEM43 variants, including eight (57%) with the pathogenic p.Ser358Leu variant (six female patients; mean age, 33 years ± 15 [SD]) and six (43%) with a TMEM43 variant of unknown significance (three female patients; mean age, 38 years ± 11). MRI findings demonstrated left ventricular systolic dysfunction in eight (57%) patients and right ventricular dysfunction in four (29%) patients. Among the nine patients with late gadolinium enhancement imaging, left ventricular late gadolinium enhancement was present in seven (78%; all subepicardial) patients. In summary, TMEM43 variants are associated with high prevalence of subepicardial late gadolinium enhancement and left ventricular dysfunction. Keywords: Arrhythmogenic Cardiomyopathy, Arrhythmogenic Right Ventricular Cardiomyopathy, TMEM43, Cardiac MRI, Genetic Variants Supplemental material is available for this article.

Sparing the Prod: Providing an Alternative to Endomyocardial Biopsies With Noninvasive Surveillance After Heart Transplantation During COVID-19.

Background: 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. Methods: 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. Results: 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. Conclusions: 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.

Contexte: 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. Méthodologie: 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. Résultats: 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. Conclusions: 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.

Left Ventricular Assist Device Support for Fabry Cardiomyopathy: A Case Series.

Patients with restrictive cardiomyopathy due to Fabry disease are often deemed ineligible for left ventricular assist device (LVAD) support due to the risk of suction events with a small LV cavity. We describe the first case series of LVAD support for Fabry disease. LVAD therapy can improve survival, quality of life, and provide clinical stability to start enzyme replacement therapy. Precautions at the time of surgery include rapid treatment of fever to avoid Fabry crises, involvement of a multidisciplinary team, and early initiation of rehabilitation. We describe LVAD support for both bridging and destination therapy.

Les patients qui ont une cardiomyopathie restrictive due à la maladie de Fabry sont souvent considérés non admissibles aux dispositifs d'assistance ventriculaire gauche (DAVG) en raison du risque de succion lié à la petite cavité VG. Nous décrivons la première série de cas liée aux DAVG en présence de la maladie de Fabry. La thérapie par DAVG peut contribuer à l'amélioration de la survie, de la qualité de vie et offrir une stabilité clinique pour débuter l'enzymothérapie de substitution. Parmi les précautions à prendre au moment de l'intervention chirurgicale figurent le traitement rapide de la fièvre pour éviter les crises de Fabry, la participation de l'équipe multidisciplinaire et la mise en place précoce de la réadaptation. Nous décrivons l'utilisation du DAVG à titre de pont jusqu'à la transplantation et à titre de thérapie définitive.

Survival Outcomes After Heart Transplantation: Does Recipient Sex Matter?

BACKGROUND: Currently, women represent <25% of heart transplant recipients. Reasons for this female underrepresentation have been attributed to selection and referral bias and potentially poorer outcomes in female recipients. The aim of this study was to compare long-term posttransplant survival between men and women, when matched for recipient and donor characteristics. METHODS AND RESULTS: Using the International Society for Heart and Lung Transplantation Registry, we performed descriptive analyses and estimated overall freedom from posttransplant death stratified by sex using Kaplan-Meier survival methods. Male and female recipients were matched according to the Index for Mortality Prediction After Cardiac Transplantation and Donor Risk Index score using 1:1 propensity score matching. The study cohort comprised 34 198 heart transplant recipients (76.3% men, 23.7% women) between 2004 and 2014. Compared with men, women were more likely younger (51 [39-59] versus 55 [46-61] years; P<0.001) and had a different distribution of heart failure etiology (P<0.001). In general, the prevalence of comorbidities was lower in women than in men. Women were less likely to have diabetes mellitus (19.1% versus 26.2%; P<0.001), hypertension (40.7% versus 47.9%; P<0.001), peripheral vascular disease (2.4% versus 3.3%; P=0.002), tobacco use (36.5% versus 52.3%; P<0.001), and prior cardiovascular surgery (38.6% versus 50.7%; P<0.001). Women were more likely to have a history of malignancy (10.5% versus 5.3%; P<0.001), require intravenous inotropes (41.4% versus 37.2%; P<0.001), and were less likely supported by an intra-aortic balloon pump (3.3% versus 3.8%; P=0.03) or durable ventricular assist device (22% versus 31.5%; P<0.001). Transplanted male recipients had a higher Index for Mortality Prediction After Cardiac Transplantation score (5 [2-7] versus 4 [1-6]; P<0.001). When male and female heart transplant recipients were matched for recipient and donor characteristics, there was no significant survival difference (P=0.57). CONCLUSIONS: Overall survival does not differ between men and women after cardiac transplantation. Women who survive to heart transplantation appear to have lower risk features than male recipients but receive hearts from higher risk donors.

A novel therapy for an unusual problem: IL-1 receptor antagonist for recurrent post-transplant pericarditis.

Heart transplant (HTx) recipients are at increased risk of pericardial disease. Idiopathic recurrent pericarditis has not been previously described following HTx. We describe a 35-year-old male who was admitted with pericarditis and moderate pericardial effusion 10 months after HTx. Two weeks before his admission, his prednisone had been tapered off. A thorough infectious workup and endomyocardial biopsy was unrevealing. He was started on colchicine with the addition of tapering prednisone regimen of 40 mg daily due to unresolved pain. Over the next several years, he had three recurrent episodes of pericarditis requiring re-initiation of prednisone with extensive investigations negative for rejection, autoimmune, and infectious causes. Cardiac MRI confirmed pericardial inflammation. Due to his recurrent course and inability to wean off prednisone, anakinra, an IL-1 receptor antagonist, was started at 100 mg sc daily. This allowed successful discontinuation of prednisone. He is now 34 months post-transplant without recurrence on anakinra and colchicine maintenance. Due to the overlap between idiopathic recurrent pericarditis and auto-inflammatory diseases, there is growing evidence for utilizing IL-1 receptor antagonists in this condition. While pericarditis is common in the HTx population, this is the first report of successful use of an IL-1 receptor blocker for pericarditis in this population.

Risk evaluation using gene expression screening to monitor for acute cellular rejection in heart transplant recipients.

BACKGROUND: Gene expression profiling (GEP) was developed for non-invasive surveillance of acute cellular rejection. Despite its widespread use, there has been a paucity in outcome data for patients managed with GEP outside of clinical trials. METHODS: The Outcomes AlloMap Registry (OAR) is an observational, prospective, multicenter study including patients aged ≥ 15 years and ≥ 55 days post-cardiac transplant. Primary outcome was death and a composite outcome of hemodynamically significant rejection, graft dysfunction, retransplantation, or death. Secondary outcomes included readmission rates and development of coronary allograft vasculopathy and malignancies. RESULTS: The study included 1,504 patients, who were predominantly Caucasian (69%), male (74%), and aged 54.1 ± 12.9 years. The prevalence of moderate to severe acute cellular rejection (≥2R) was 2.0% from 2 to 6 months and 2.2% after 6 months. In the OAR there was no association between higher GEP scores and coronary allograft vasculopathy (p = 0.25), cancer (p = 0.16), or non-cytomegalovirus infection (p = 0.10). Survival at 1, 2, and 5 years post-transplant was 99%, 98%, and 94%, respectively. The composite outcome occurred in 103 patients during the follow-up period. GEP scores in dual-organ recipients (heart-kidney and heart-liver) were comparable to heart-alone recipients. CONCLUSIONS: This registry comprises the largest contemporary cohort of patients undergoing GEP for surveillance. Among patients selected for GEP surveillance, survival is excellent, and rates of acute rejection, graft dysfunction, readmission, and death are low.

Renal thrombotic microangiopathy and pulmonary arterial hypertension in a patient with late-onset cobalamin C deficiency.

Cobalamin C (cblC) deficiency is the most commonly inherited inborn error of vitamin B12 metabolism. It is characterized by multisystem involvement with severe neurological, hematological, renal and cardiopulmonary manifestations. Disease is most commonly diagnosed early in the first decade of life. We report a case of a 20-year-old woman who developed severe pulmonary arterial hypertension while under nephrologic follow-up for chronic kidney disease. She had initially presented at 14 years of age with visual disturbance and acute renal failure and been diagnosed with thrombotic thrombocytopenic purpura on the basis of kidney biopsy findings of thrombotic microangiopathy and compatible ADAMTS13 (a disentegrin and metalloproteinase with a thrombospondin type 1 motif member 13). When cblC deficiency was eventually diagnosed, remarkable improvement in cardiopulmonary function was evident upon initiation of treatment. This case highlights the importance of a timely diagnosis and initiation of treatment for cblC deficiency. Clinical diagnosis may be challenged by asynchronous organ symptom presentation and by misleading laboratory tests, in this case: an initial low ADAMTS13. A simple test of plasma homocysteine level should be encouraged in cases of thrombotic microangiopathy and/or pulmonary artery hypertension.

The prognostic significance of frailty compared to peak oxygen consumption and B-type natriuretic peptide in patients with advanced heart failure.

Frailty assessment has become an integral part of the evaluation of potential candidates for heart transplantation and ventricular assist device (HTx/VAD). The impact of frailty, as a heart failure risk factor or to identify those who will derive the greatest benefit with HTx/VAD remains unclear. The aim of this study was to evaluate the independent prognostic relevance of frailty assessment from peak oxygen consumption (peak VO2 ) or B-type natriuretic peptide (BNP) on mortality in patients referred for advanced heart failure therapies. Frailty was measured using modified Fried frailty criteria. In 201 consecutive patients, during a median follow-up of 17.5 months (IQR 11-29.2), there were 25 (12.4%) deaths. One-year survival was 100%, 94%, and 78% in nonfrail, prefrail, and frail patients, respectively (log rank P = .0001). Frailty was associated with a twofold increase risk of death (HR 2.01, P < .0001, 95% CI 1.42-2.84). When adjusted for BNP or peak VO2 , frailty was not associated with a significant risk of all-cause death. However, when peak VO2 is stratified into two categories (≥12 mL/kg/min vs <12 mL/kg/min), frailty was associated with increased mortality in patients with a lower peak VO2 (HR 1.72, P = .006).

Early pneumopericardium after heart transplantation.

A 60-year-old woman with a history of dilated cardiomyopathy underwent heart transplantation. One month post discharge, she presented to clinic with low-grade fever and productive cough. Her chest radiograph showed air-fluid levels in the pericardial silhouette. Transthoracic echocardiogram showed a large complex pericardial collection with no evidence of cardiac tamponade. The patient was urgently taken to the operating room for exploration. A large "egg-shaped" mass in the pericardium measuring 10 × 12 cm with gaseous material was aspirated. As the posterior wall of the mass was firmly adhered to the right atrium, the capsule was incompletely excised. We present the case of a potentially life-threatening complication post transplantation that required surgical debridement and life-long antibiotic suppressive therapy. To our knowledge, this is the first report of purulent pericardial collection caused by Enterobacter cancerogenous. Further research is required to better understand the biology of this microorganism and the role it may play as a pathogen in immunocompromised patients following solid organ transplantation.

Paying more than lip service to an oral lesion: a case of plasmablastic lymphoma.

Plasmablastic lymphoma (PBL) is a variant of lymphoma originally described in the oral cavity of patients with advanced HIV. Our patient developed PBL despite well-controlled HIV and a CD4 count greater than 800 cells/µl. A drug interaction with an inhaled corticosteroid and ritonavir likely contributed to the development of this malignancy through increased immune suppression.