Immunology of THymectomy And childhood CArdiac transplant (ITHACA): protocol for a UK-wide prospective observational cohort study to identify immunological risk factors of post-transplant lymphoproliferative disease (PTLD) in thymectomised children.

INTRODUCTION: Paediatric heart transplant patients are disproportionately affected by Epstein-Barr virus (EBV)-related post-transplant lymphoproliferative disease (PTLD) compared with other childhood solid organ recipients. The drivers for this disparity remain poorly understood. A potential risk factor within this cohort is the routine surgical removal of the thymus-a gland critical for the normal development of T-lymphocyte-mediated antiviral immunity-in early life, which does not occur in other solid organ transplant recipients. Our study aims to describe the key immunological differences associated with early thymectomy, its impact on the temporal immune response to EBV infection and subsequent risk of PTLD. METHODS AND ANALYSIS: Prospective and sequential immune monitoring will be performed for 34 heart transplant recipients and 6 renal transplant patients (aged 0-18 years), stratified into early (<1 year), late (>1 year) and non-thymectomy groups. Peripheral blood samples and clinical data will be taken before transplant and at 3, 6, 12 and 24 months post-transplant. Single cell analysis of circulating immune cells and enumeration of EBV-specific T-lymphocytes will be performed using high-dimensional spectral flow cytometry with peptide-Major Histocompatibilty Complex (pMHC) I/II tetramer assay, respectively. The functional status of EBV-specific T-lymphocytes, along with EBV antibodies and viral load will be monitored at each of the predefined study time points. ETHICS AND DISSEMINATION: Ethical approval for this study has been obtained from the North of Scotland Research Ethics Committee. The results will be disseminated through publications in peer-reviewed journals, presentations at scientific conferences and patient-centred forums, including social media. TRIAL REGISTRATION NUMBER: ISRCTN10096625.

Heart transplantation in children and adults with Down syndrome: A single centre experience.

BACKGROUND: In recent years, rapid advances in cardiac surgery and changes in attitude towards patients with cognitive disability have led to these patients receiving cardiac transplantation. METHOD: This is a retrospective report describing the experience of four patients with Down Syndrome who received heart transplantation in a single institution. RESULTS: Anthracycline-induced cardiomyopathy was the most common cause of heart failure in this group (3/4). Two patients were bridged to transplantation, one by using a combination of extra-corporeal membrane oxygenation and biventricular assist device and the other by using a durable implantable left ventricular assist device. All the four patients are alive with the longest surviving patient 17 years after transplantation. Against strong hypothetical predictions, we observed no propensity for the development of post-transplant infections or lymphoproliferative disorders. CONCLUSION: Down Syndrome should not be the sole contraindication to heart transplantation. The decision for transplantation should be on a case-by-case basis provided adequate social support is in place.

Impact of valve morphology, hypertension and age on aortic wall properties in patients with coarctation: a two-centre cross-sectional study.

OBJECTIVE: We aimed to investigate the combined effects of arterial hypertension, bicuspid aortic valve disease (BAVD) and age on the distensibility of the ascending and descending aortas in patients with aortic coarctation. DESIGN: Cross-sectional study. SETTING: The study was conducted at two university medical centres, located in Berlin and London. PARTICIPANTS: A total of 121 patients with aortic coarctation (ages 1-71 years) underwent cardiac MRI, echocardiography and blood pressure measurements. OUTCOME MEASURES: Cross-sectional diameters of the ascending and descending aortas were assessed to compute aortic area distensibility. Findings were compared with age-specific reference values. The study complied with the Strengthening the Reporting of Observational Studies in Epidemiology statement and reporting guidelines. RESULTS: Impaired distensibility (below fifth percentile) was seen in 37% of all patients with coarctation in the ascending aorta and in 43% in the descending aorta. BAVD (43%) and arterial hypertension (72%) were present across all ages. In patients >10 years distensibility impairment of the ascending aorta was predominantly associated with BAVD (OR 3.1, 95% CI 1.33 to 7.22, p=0.009). Distensibility impairment of the descending aorta was predominantly associated with arterial hypertension (OR 2.8, 95% CI 1.08 to 7.2, p=0.033) and was most pronounced in patients with uncontrolled hypertension despite antihypertensive treatment. CONCLUSION: From early adolescence on, both arterial hypertension and BAVD have a major impact on aortic distensibility. Their specific effects differ in strength and localisation (descending vs ascending aorta). Moreover, adequate blood pressure control is associated with improved distensibility. These findings could contribute to the understanding of cardiovascular complications and the management of patients with aortic coarctation.

Paediatric donation after circulatory determined death heart transplantation using donor normothermic regional perfusion and ex situ heart perfusion: A case report.

This is a report of a unique DCD paediatric heart transplant whereby normothermic regional perfusion was used to assess DCD heart function after death followed by ex situ heart perfusion of the graft during transportation from donor to recipient hospitals. The DCD donor was a 9-year-old boy weighing 84 kg. The recipient was 7-year-old boy with failing Fontan circulation and weighed 23 kg. It was an ABO-compatible heart transplantation. The DCD heart was reperfused and assessed using normothermic regional perfusion followed by portable ex situ heart perfusion during transportation. The orthotopic heart transplantation was successful with good graft function and no evidence of rejection on endomyocardial biopsy at 30 days post-transplant. At 1-year follow-up, excellent graft function is maintained, and he is attending school with a good quality of life. DCD heart transplantation in children is a promising solution to reducing paediatric waiting times. The case demonstrates the feasibility of using normothermic regional perfusion in the donor and ex situ heart perfusion during graft transportation. This combination allowed a functional assessment whilst minimizing warm ischaemia resulting in a successful outcome. More research and long-term follow-up are needed in order to benefit from the huge potential that paediatric DCD heart transplantation has to offer.

A comprehensive characterization of myocardial and vascular phenotype in pediatric chronic kidney disease using cardiovascular magnetic resonance imaging.

BACKGROUND: Children with chronic kidney disease (CKD) have increased cardiovascular mortality. Identifying high-risk children who may benefit from further therapeutic intervention is difficult as cardiovascular abnormalities are subtle. Although transthoracic echocardiography may be used to detect sub-clinical abnormalities, it has well-known problems with reproducibility that limit its ability to accurately detect these changes. Cardiovascular magnetic resonance (CMR) is the reference standard method for assessing blood flow, cardiac structure and function. Furthermore, recent innovations enable the assessment of radial and longitudinal myocardial velocity, such that detection of sub-clinical changes is now possible. Thus, CMR may be ideal for cardiovascular assessment in pediatric CKD. This study aims to comprehensively assess cardiovascular function in pediatric CKD using CMR and determine its relationship with CKD severity. METHODS: A total of 120 children (40 mild, 40 moderate, 20 severe pre-dialysis CKD subjects and 20 healthy controls) underwent CMR with non-invasive blood pressure (BP) measurements. Cardiovascular parameters measured included systemic vascular resistance (SVR), total arterial compliance (TAC), left ventricular (LV) structure, ejection fraction (EF), cardiac timings, radial and longitudinal systolic and diastolic myocardial velocities. Between group comparisons and regression modelling were used to identify abnormalities in CKD and determine the effects of renal severity on myocardial function. RESULTS: The elevation in mean BP in CKD was accompanied by significantly increased afterload (SVR), without evidence of arterial stiffness (TAC) or increased fluid overload. Left ventricular volumes and global function were not abnormal in CKD. However, there was evidence of LV remodelling, prolongation of isovolumic relaxation time and reduced systolic and diastolic myocardial velocities. CONCLUSION: Abnormal cardiovascular function is evident in pre-dialysis pediatric CKD. Novel CMR biomarkers may be useful for the detection of subtle abnormalities in this population. Further studies are needed to determine to prognostic value of these biomarkers.

Detecting Clinically Meaningful Shape Clusters in Medical Image Data: Metrics Analysis for Hierarchical Clustering Applied to Healthy and Pathological Aortic Arches.

OBJECTIVE: Today's growing medical image databases call for novel processing tools to structure the bulk of data and extract clinically relevant information. Unsupervised hierarchical clustering may reveal clusters within anatomical shape data of patient populations as required for modern precision medicine strategies. Few studies have applied hierarchical clustering techniques to three-dimensional patient shape data and results depend heavily on the chosen clustering distance metrics and linkage functions. In this study, we sought to assess clustering classification performance of various distance/linkage combinations and of different types of input data to obtain clinically meaningful shape clusters. METHODS: We present a processing pipeline combining automatic segmentation, statistical shape modeling, and agglomerative hierarchical clustering to automatically subdivide a set of 60 aortic arch anatomical models into healthy controls, two groups affected by congenital heart disease, and their respective subgroups as defined by clinical diagnosis. Results were compared with traditional morphometrics and principal component analysis of shape features. RESULTS: Our pipeline achieved automatic division of input shape data according to primary clinical diagnosis with high F-score (0.902 ± 0.042) and Matthews correlation coefficient (0.851 ± 0.064) using the correlation/weighted distance/linkage combination. Meaningful subgroups within the three patient groups were obtained and benchmark scores for automatic segmentation and classification performance are reported. CONCLUSION: Clustering results vary depending on the distance/linkage combination used to divide the data. Yet, clinically relevant shape clusters and subgroups could be found with high specificity and low misclassification rates. SIGNIFICANCE: Detecting disease-specific clusters within medical image data could improve image-based risk assessment, treatment planning, and medical device development in complex disease.

Abnormal Wave Reflections and Left Ventricular Hypertrophy Late After Coarctation of the Aorta Repair.

Patients with repaired coarctation of the aorta are thought to have increased afterload due to abnormalities in vessel structure and function. We have developed a novel cardiovascular magnetic resonance protocol that allows assessment of central hemodynamics, including central aortic systolic blood pressure, resistance, total arterial compliance, pulse wave velocity, and wave reflections. The main study aims were to (1) characterize group differences in central aortic systolic blood pressure and peripheral systolic blood pressure, (2) comprehensively evaluate afterload (including wave reflections) in the 2 groups, and (3) identify possible biomarkers among covariates associated with elevated left ventricular mass (LVM). Fifty adult patients with repaired coarctation and 25 age- and sex-matched controls were recruited. Ascending aorta area and flow waveforms were obtained using a high temporal-resolution spiral phase-contrast cardiovascular magnetic resonance flow sequence. These data were used to derive central hemodynamics and to perform wave intensity analysis noninvasively. Covariates associated with LVM were assessed using multivariable linear regression analysis. There were no significant group differences (P≥0.1) in brachial systolic, mean, or diastolic BP. However central aortic systolic blood pressure was significantly higher in patients compared with controls (113 versus 107 mm Hg, P=0.002). Patients had reduced total arterial compliance, increased pulse wave velocity, and larger backward compression waves compared with controls. LVM index was significantly higher in patients than controls (72 versus 59 g/m2, P<0.0005). The magnitude of the backward compression waves was independently associated with variation in LVM (P=0.01). Using a novel, noninvasive hemodynamic assessment, we have shown abnormal conduit vessel function after coarctation of the aorta repair, including abnormal wave reflections that are associated with elevated LVM.

How successful is successful? Aortic arch shape after successful aortic coarctation repair correlates with left ventricular function.

OBJECTIVES: Even after successful aortic coarctation repair, there remains a significant incidence of late systemic hypertension and other morbidities. Independently of residual obstruction, aortic arch morphology alone may affect cardiac function and outcome. We sought to uncover the relationship of arch 3-dimensional shape features with functional data obtained from cardiac magnetic resonance scans. METHODS: Three-dimensional aortic arch shape models of 53 patients (mean age, 22.3 ± 5.6 years) 12 to 38 years after aortic coarctation repair were reconstructed from cardiac magnetic resonance data. A novel validated statistical shape analysis method computed a 3-dimensional mean anatomic shape of all aortic arches and calculated deformation vectors of the mean shape toward each patient's arch anatomy. From these deformations, 3-dimensional shape features most related to left ventricular ejection fraction, indexed left ventricular end-diastolic volume, indexed left ventricular mass, and resting systolic blood pressure were extracted from the deformation vectors via partial least-squares regression. RESULTS: Distinct arch shape features correlated significantly with left ventricular ejection fraction (r = 0.42, P = .024), indexed left ventricular end-diastolic volume (r = 0.65, P < .001), and indexed left ventricular mass (r = 0.44, P = .014). Lower left ventricular ejection fraction, larger indexed left ventricular end-diastolic volume, and increased indexed left ventricular mass were identified with an aortic arch shape that has an elongated ascending aorta with a high arch height-to-width ratio, a relatively short proximal transverse arch, and a relatively dilated descending aorta. High blood pressure seemed to be linked to gothic arch shape features, but this did not achieve statistical significance. CONCLUSIONS: Independently of hemodynamically important arch obstruction or residual aortic coarctation, specific aortic arch shape features late after successful aortic coarctation repair seem to be associated with worse left ventricular function. Analyzing 3-dimensional shape information via statistical shape modeling can be an adjunct to long-term risk assessment in patients after aortic coarctation repair.

MRI as a tool for non-invasive vascular profiling: a pilot study in patients with aortic coarctation.

AIM: While the overall concept of aortic coarctation has changed from one of simple obstruction to one that includes significant vascular dysfunction, this has not yet been translated into the diagnostic and treatment process. To close this gap, we sought to demonstrate the usefulness of an additional non-invasive vascular profile. METHOD: During a pilot study in eight coarctation patients, aortic area compliance, aortic distensibility, time phase shift and blood flow (distribution) were calculated from cine-MRI and 2D-/4D-velocity-encoded MRI sequences. RESULTS: Compared to healthy individuals, a significantly lower aortic compliance and reduced flow to the descending aorta were found in patients with coarctation. DISCUSSION: These differences underline the potential usefulness of a combined vascular profile in coarctation patients. CONCLUSION: It was successfully shown that functional vascular profiling of the aorta is feasible to be acquired non-invasively in a clinical setting and can provide additional diagnostic information. These can be the key input parameters for computational fluid dynamics-modeling.

Rapid breath-hold assessment of myocardial velocities using spiral UNFOLD-ed SENSE tissue phase mapping.

PURPOSE: To develop and validate a rapid breath-hold tissue phase mapping (TPM) sequence. MATERIALS AND METHODS: The sequence was based on an efficient uniform density spiral acquisition, combined with data acceleration. A novel acquisition and reconstruction strategy enabled combination of UNFOLD (2×) and SENSE (3×): UNFOLD-ed SENSE. The sequence was retrospectively cardiac-gated, and a graphics processing unit (GPU) was used for rapid "online" reconstruction. The optimal UNFOLD parameters for the data were calculated using an in silico model. The technique was validated on a 1.5T MR scanner in 15 patients with known aortic valve disease, against a respiratory self-navigated free-breathing TPM technique. Quantitative image quality measures (velocity-to-noise and edge sharpness) were made as well as calculation of longitudinal, radial, and tangential myocardial velocities in the left ventricle. RESULTS: The proposed breath-hold TPM data took eight heartbeats to acquire. The breath-hold TPM images had significantly higher edge sharpness (P = 0.0014) than the self-navigated TPM images, but with significantly lower velocity-to-noise ratio (P < 0.0001). There was excellent agreement (r > 0.94) in the longitudinal, radial, and tangential velocities between the self-navigated data and the proposed breath-hold TPM sequence. CONCLUSION: We demonstrate the feasibility of using spiral UNFOLD-ed SENSE to measure myocardial velocities using a rapid breath-hold spiral TPM sequence. This novel technique might enable accurate measurement of myocardial velocities, in a short scan time, which is especially important in a busy clinical workflow. J. MAGN. RESON. IMAGING 2016;44:1003-1009.