Transplantation of hearts retrieved from donation after circulatory death (DCD) donors is an evolving clinical practice.
The purpose of this study is to provide an update on the authors’ Australian ...clinical program and discuss lessons learned since performing the world’s first series of distantly procured DCD heart transplants.
The authors report their experience of 23 DCD heart transplants from 45 DCD donor referrals since 2014. Donor details were collected using electronic donor records (Donate Life, Australia) and all recipient details were collected from clinical notes and electronic databases at St. Vincent’s Hospital.
Hearts were retrieved from 33 of 45 DCD donors. A total of 12 donors did not progress to circulatory arrest within the pre-specified timeframe. Eight hearts failed to meet viability criteria during normothermic machine perfusion, and 2 hearts were declined due to machine malfunction. A total of 23 hearts were transplanted between July 2014 and April 2018. All recipients had successful implantation, with mechanical circulatory support utilized in 9 cases. One case requiring extracorporeal membrane oxygenation subsequently died on the sixth post-operative day, representing a mortality of 4.4% over 4 years with a total follow-up period of 15,500 days for the entire cohort. All surviving recipients had normal cardiac function on echocardiogram and no evidence of acute rejection on discharge. All surviving patients remain in New York Heart Association functional class I with normal biventricular function.
DCD heart transplant outcomes are excellent. Despite a higher requirement for mechanical circulatory support for delayed graft function, primarily in recipients with ventricular assist device support, overall survival and rejection episodes are comparable to outcomes from contemporary brain-dead donors.
Display omitted
Timely referrals for transplantation and left ventricular assist device implantation play a key role in favorable outcomes in patients with advanced heart failure. Nonetheless, evaluation usually ...occurs at advanced heart failure centers and is obscured from referring physicians. The purposes of this review are to explain the decision-making process for candidacy for advanced therapies and to describe the potential impact of the new organ allocation algorithm on center decision making. The document first addresses the signs of advanced heart failure, specifically focusing on the importance of the syndrome of low cardiac output as a key feature of advanced heart failure, and then summarizes the evaluation as a 3-step process addressing the following questions: 1) Is transplantation or durable assist device placement indicated? 2) Are there contraindications to either intervention? 3) How can one choose between transplantation and left ventricular assist device implantation if advanced therapies are indicated and not contraindicated?
Standardized donor‐derived cell‐free DNA (dd‐cfDNA) testing has been introduced into clinical use to monitor kidney transplant recipients for rejection. This report describes the performance of this ...dd‐cfDNA assay to detect allograft rejection in samples from heart transplant (HT) recipients undergoing surveillance monitoring across the United States. Venous blood was longitudinally sampled from 740 HT recipients from 26 centers and in a single‐center cohort of 33 patients at high risk for antibody‐mediated rejection (AMR). Plasma dd‐cfDNA was quantified by using targeted amplification and sequencing of a single nucleotide polymorphism panel. The dd‐cfDNA levels were correlated to paired events of biopsy‐based diagnosis of rejection. The median dd‐cfDNA was 0.07% in reference HT recipients (2164 samples) and 0.17% in samples classified as acute rejection (35 samples; P = .005). At a 0.2% threshold, dd‐cfDNA had a 44% sensitivity to detect rejection and a 97% negative predictive value. In the cohort at risk for AMR (11 samples), dd‐cfDNA levels were elevated 3‐fold in AMR compared with patients without AMR (99 samples, P = .004). The standardized dd‐cfDNA test identified acute rejection in samples from a broad population of HT recipients. The reported test performance characteristics will guide the next stage of clinical utility studies of the dd‐cfDNA assay.
A large multicenter study in a broad heart transplant surveillance population demonstrates the ability of standardized donor‐ derived cell‐free DNA testing to identify both T cell–mediated and antibody‐mediated acute rejection with a high negative predictive value.
Well-designed randomized controlled trials (RCTs) testing efficacy of post-transplant medication adherence enhancing interventions and clinical outcomes are scarce.
This randomized controlled trial ...enrolled adult heart, liver, and lung transplant recipients who were >1 year post-transplant and on tacrolimus twice daily (convenience sample) (visit 1). After a 3-month run-in period, patients were randomly assigned 1:1 to intervention group (IG) or control group (CG) (visit 2), followed by a 6-month intervention (visits 2-4) and a 6-month adherence follow-up period (visit 5). All patients used electronic monitoring for 15 months for adherence measurement, generating a daily binary adherence score per patient. Post-intervention 5-year clinical event-free survival (mortality or retransplantation) was evaluated. The IG received staged multicomponent tailored behavioral interventions (visits 2-4) building on social cognitive theory and trans-theoretical model (e.g., electronic monitoring feedback, motivational interviewing). The CG received usual care and attended visits 1-5 only. Intention-to-treat analysis used generalized estimating equation modeling and Kaplan-Meier survival analysis.
Of 247 patients, 205 were randomly assigned (103 IG, 102 CG). At baseline, average daily proportions of patients with correct dosing (82.6% IG, 78.4% CG) and timing adherence (75.8% IG, 72.2% CG) were comparable. The IG had a 16% higher dosing adherence post-intervention (95.1% IG, 79.1% CG; p < 0.001), resulting in odds of adherence being 5 times higher in the IG than in the CG (odds ratio 5.17, 95% confidence interval 2.86-9.38). This effect was sustained at end of follow-up (similar results for timing adherence). In the IG, 5-year clinical event-free survival was 82.5% vs 72.5% in the CG (p = 0.18).
Our intervention was efficacious in improving adherence and sustainable. Further research should investigate clinical impact, cost-effectiveness, and scalability.
Malignancy is a concern in cardiac transplant recipients, but the temporal trends of de novo malignancy development are unknown.
The goal of this study was to describe the temporal trends of the ...incidence, types, and predictors of de novo malignancy in cardiac transplant recipients.
The authors analyzed the temporal trends of post-transplant incidence, types, and predictors of malignancy using 17,587 primary adult heart-only transplant recipients from the International Society for Heart and Lung Transplantation registry. The main study outcomes included the incidence of, types of, and time to de novo malignancy.
The risk of any de novo solid malignancy between years 1 and 5 after transplantation was 10.7%. The cumulative incidence by malignancy type was: skin cancer (7.0%), non-skin solid cancer (4.0%), and lymphoproliferative disorders (0.9%). There was no temporal difference in the time to development according to malignancy type. However, the cumulative incidence of de novo solid malignancy increased from 2000 to 2005 vs. 2006 to 2011 (10.0% vs. 12.4%; p < 0.0001). Survival in patients after de novo malignancy was markedly lower than in patients without malignancy (p < 0.0001). Older recipients and patients who underwent transplantation in the recent era had a higher risk of de novo malignancy.
More than 10% of adult heart transplant recipients developed de novo malignancy between years 1 and 5 after transplantation, and this outcome was associated with increased mortality. The incidence of post-transplant de novo solid malignancy increased temporally, with the largest increase in skin cancer. Individualized immunosuppression strategies and enhanced cancer screening should be studied to determine whether they can reduce the adverse outcomes of post-transplantation malignancy.
Display omitted
The cohort of long-term survivors of heart transplant is expanding, and the assessment of these patients requires specific knowledge of the surgical techniques employed to implant the donor heart, ...the physiology of the transplanted heart, complications of invasive tests routinely performed to detect graft rejection (GR), and the specific pathologies that may affect the transplanted heart. A joint EACVI/Brazilian cardiovascular imaging writing group committee has prepared these recommendations to provide a practical guide to echocardiographers involved in the follow-up of heart transplant patients and a framework for standardized and efficient use of cardiovascular imaging after heart transplant. Since the transplanted heart is smaller than the recipient's dilated heart, the former is usually located more medially in the mediastinum and tends to be rotated clockwise. Therefore, standard views with conventional two-dimensional (2D) echocardiography are often difficult to obtain generating a large variability from patient to patient. Therefore, in echocardiography laboratories equipped with three-dimensional echocardiography (3DE) scanners and specific expertise with the technique, 3DE may be a suitable alternative to conventional 2D echocardiography to assess the size and the function of cardiac chambers. 3DE measurement of left (LV) and right ventricular (RV) size and function are more accurate and reproducible than conventional 2D calculations. However, clinicians should be aware that cardiac chamber volumes obtained with 3DE cannot be compared with those obtained with 2D echocardiography. To assess cardiac chamber morphology and function during follow-up studies, it is recommended to obtain a comprehensive echocardiographic study at 6 months from the cardiac transplantation as a baseline and make a careful quantitation of cardiac chamber size, RV systolic function, both systolic and diastolic parameters of LV function, and pulmonary artery pressure. Subsequent echocardiographic studies should be interpreted in comparison with the data obtained from the 6-month study. An echocardiographic study, which shows no change from the baseline study, has a high negative predictive value for GR. There is no single systolic or diastolic parameter that can be reliably used to diagnose GR. However, in case several parameters are abnormal, the likelihood of GR increases. When an abnormality is detected, careful revision of images of the present and baseline study (side-by-side) is highly recommended. Global longitudinal strain (GLS) is a suitable parameter to diagnose subclinical allograft dysfunction, regardless of aetiology, by comparing the changes occurring during serial evaluations. Evaluation of GLS could be used in association with endomyocardial biopsy (EMB) to characterize and monitor an acute GR or global dysfunction episode. RV size and function at baseline should be assessed using several parameters, which do not exclusively evaluate longitudinal function. At follow-up echocardiogram, all these parameters should be compared with the baseline values. 3DE may provide a more accurate and comprehensive assessment of RV size and function. Moreover, due to the unpredictable shape of the atria in transplanted patients, atrial volume should be measured using the discs' summation algorithm (biplane algorithm for the left atrium) or 3DE. Tricuspid regurgitation should be looked for and properly assessed in all echocardiographic studies. In case of significant changes in severity of tricuspid regurgitation during follow-up, a 2D/3D and colour Doppler assessment of its severity and mechanisms should be performed. Aortic and mitral valves should be evaluated according to current recommendations. Pericardial effusion should be serially evaluated regarding extent, location, and haemodynamic impact. In case of newly detected pericardial effusion, GR should be considered taking into account the overall echocardiographic assessment and patient evaluation. Dobutamine stress echocardiography might be a suitable alternative to routine coronary angiography to assess cardiac allograft vasculopathy (CAV) at centres with adequate experience with the methodology. Coronary flow reserve and/or contrast infusion to assess myocardial perfusion might be combined with stress echocardiography to improve the accuracy of the test. In addition to its role in monitoring cardiac chamber function and in diagnosis the occurrence of GR and/or CAV, in experienced centres, echocardiography might be an alternative to fluoroscopy to guide EMB, particularly in children and young women, since echocardiography avoids repeated X-ray exposure, permits visualization of soft tissues and safer performance of biopsies of different RV regions. Finally, in addition to the indications about when and how to use echocardiography, the document also addresses the role of the other cardiovascular imaging modalities during follow-up of heart transplant patients. In patients with inadequate acoustic window and contraindication to contrast agents, pharmacological SPECT is an alternative imaging modality to detect CAV in heart transplant patients. However, in centres with adequate expertise, intravascular ultrasound (IVUS) in conjunction with coronary angiography with a baseline study at 4-6 weeks and at 1 year after heart transplant should be performed to exclude donor coronary artery disease, to detect rapidly progressive CAV, and to provide prognostic information. Despite the fact that coronary angiography is the current gold-standard method for the detection of CAV, the use of IVUS should also be considered when there is a discrepancy between non-invasive imaging tests and coronary angiography concerning the presence of CAV. In experienced centres, computerized tomography coronary angiography is a good alternative to coronary angiography to detect CAV. In patients with a persistently high heart rate, scanners that provide high temporal resolution, such as dual-source systems, provide better image quality. Finally, in patients with insufficient acoustic window, cardiac magnetic resonance is an alternative to echocardiography to assess cardiac chamber volumes and function and to exclude acute GR and CAV in a surveillance protocol.
Older organs represent an untapped potential to close the gap between demand and supply in organ transplantation but are associated with age-specific responses to injury and increased immunogenicity, ...thereby aggravating transplant outcomes. Here we show that cell-free mitochondrial DNA (cf-mt-DNA) released by senescent cells accumulates with aging and augments immunogenicity. Ischemia reperfusion injury induces a systemic increase of cf-mt-DNA that promotes dendritic cell-mediated, age-specific inflammatory responses. Comparable events are observed clinically, with the levels of cf-mt-DNA elevated in older deceased organ donors, and with the isolated cf-mt-DNA capable of activating human dendritic cells. In experimental models, treatment of old donor animals with senolytics clear senescent cells and diminish cf-mt-DNA release, thereby dampening age-specific immune responses and prolonging the survival of old cardiac allografts comparable to young donor organs. Collectively, we identify accumulating cf-mt-DNA as a key factor in inflamm-aging and present senolytics as a potential approach to improve transplant outcomes and availability.
Preformed donor HLA‐specific antibodies are a known indicator for poor patient survival after cardiac transplantation. The role of de novo donor‐specific antibodies (DSA) formed after cardiac ...transplantation is less clear. Here we have retrospectively analyzed 243 cardiac transplant recipients, measuring HLA antibody production every year after transplantation up to 13 years post‐transplant. Production of de novo DSA was analyzed in patients who had been negative for DSA prior to their transplant. DSA including transient antibodies were associated with poor patient survival (p = 0.0018, HR = 3.198). However, de novo and persistent DSA was strongly associated with poor patient survival (p = 0.0001 HR = 4.351). Although complement fixing persistent DSA correlated with poor patient survival, this was not increased compared to noncomplement fixing persistent DSA. Multivariable analysis indicated de novo persistent DSA to be an independent predictor of poor patient survival along with HLA‐DR mismatch and donor age. Only increasing donor age was found to be an independent risk factor for earlier development of CAV. In conclusion, patients who are transplanted in the absence of pre‐existing DSA make de novo DSA after transplantation which are associated with poor survival. Early and regular monitoring of post‐transplant DSA is required to identify patients at risk of allograft failure.
A retrospective study of 243 cardiac transplant patients, followed annually for up to 13 years, shows that production of de novo donor‐specific HLA antibodies portends worse patient survival and is an independent risk factor for poor patient survival.
PDF
