Caution: shortcomings of traditional segmentation methods from magnetic resonance imaging brain scans intended for 3-dimensional surface modelling in children with pathology.

This technical innovation assesses the adaptability of some common automated segmentation tools on abnormal pediatric magnetic resonance (MR) brain scans. We categorized 35 MR scans by pathologic features: (1) "normal"; (2) "atrophy"; (3) "cavity"; (4) "other." The following three tools, (1) Computational Anatomy Toolbox version 12 (CAT12); (2) Statistical Parametic Mapping version 12 (SPM12); and (3) MRTool, were tested on each scan-with default and adjusted settings. Success was determined by radiologist consensus on the surface accuracy. Automated segmentation failed in scans demonstrating severe surface brain pathology. Segmentation of the "cavity" group was ineffective, with success rates of 23.1% (CAT12), 69.2% (SPM12) and 46.2% (MRTool), even with refined settings and manual edits. Further investigation is required to improve this workflow and automated segmentation methodology for complex surface pathology.

Assessment of post-infarct ventricular septal defects through 3D printing and statistical shape analysis.

Background: Post-infarct ventricular septal defect (PIVSD) is a serious complication of myocardial infarction. We evaluated 3D-printing models in PIVSD clinical assessment and the feasibility of statistical shape modeling for morphological analysis of the defects. Methods: Models (n = 15) reconstructed from computed tomography data were evaluated by clinicians (n = 8). Statistical shape modeling was performed on 3D meshes to calculate the mean morphological configuration of the defects. Results: Clinicians' evaluation highlighted the models' utility in displaying defects for interventional/surgical planning, education/training and device development. However, models lack dynamic representation. Morphological analysis was feasible and revealed oval-shaped (n = 12) and complex channel-like (n = 3) defects. Conclusion: 3D-PIVSD models can complement imaging data for teaching and procedural planning. Statistical shape modeling is feasible in this scenario.

Following heart attacks, the heart muscle becomes scarred and weaker, making it prone to tearing under high pressures. These tears are known as 'post-infarct ventricular septal defects'. Their shape varies greatly as the heart beats. The approach to fixing these can range from plugging them with a device or patching them by open heart surgery. We created 15 3D-printed models of hearts with these kinds of defects and made digital reconstructions of the tears to see the different sizes/shapes that they can have. Doctors agreed that 3D-printed models could help in planning repairs and training other doctors. The digital reconstructions of the tears showed that many were round, but some had irregular shapes which would mean devices used to fix them may not fit.

Prospective multiparametric CMR characterization and MicroRNA profiling of anthracycline cardiotoxicity: A pilot translational study.

Background: Anthracycline cardiotoxicity is a significant clinical challenge. Biomarkers to improve risk stratification and identify early cardiac injury are required. Objectives: The purpose of this pilot study was to prospectively characterize anthracycline cardiotoxicity using cardiovascular magnetic resonance (CMR), echocardiography and MicroRNAs (MiRNAs), and identify baseline predictors of LVEF recovery. Methods: Twenty-four patients (age 56 range 18-75 years; 42 % female) with haematological malignancy scheduled to receive anthracycline chemotherapy (median dose 272 mg/m2 doxorubicin equivalent) were recruited and evaluated at three timepoints (baseline, completion of chemotherapy, and 6 months after completion of chemotherapy) with multiparametric 1.5 T CMR, echocardiography and circulating miRNAs sequencing. Results: Seventeen complete datasets were obtained. CMR left ventricular ejection fraction (LVEF) fell significantly between baseline and completion of chemotherapy (61 ± 3 vs 53 ± 3 %, p < 0.001), before recovering significantly at 6-month follow-up (55 ± 3 %, p = 0.018). Similar results were observed for 3D echocardiography-derived LVEF and CMR-derived longitudinal, circumferential and radial feature-tracking strain. Patients were divided into tertiles according to LVEF recovery (poor recovery, partial recovery, good recovery). CMR-derived mitral annular plane systolic excursion (MAPSE) was significantly different at baseline in patients exhibiting poor LVEF recovery (11.7 ± 1.5 mm) in comparison to partial recovery (13.7 ± 2.7 mm), and good recovery (15.7 ± 3.1 mm; p = 0.028). Furthermore, baseline miRNA-181-5p and miRNA-221-3p expression were significantly higher in this group. T2 mapping increased significantly on completion of chemotherapy compared to baseline (54.0 ± 4.6 to 57.8 ± 4.9 ms, p = 0.001), but was not predictive of LVEF recovery. No changes to LV mass, extracellular volume fraction, T1 mapping or late gadolinium enhancement were observed. Conclusions: Baseline CMR-derived MAPSE, circulating miRNA-181-5p, and miRNA-221-3p were associated with poor recovery of LVEF 6 months after completion of anthracycline chemotherapy, suggesting their potential predictive role in this context. T2 mapping increased significantly on completion of chemotherapy but was not predictive of LVEF recovery.

Feasibility of a longitudinal statistical atlas model to study aortic growth in congenital heart disease.

Studying anatomical shape progression over time is of utmost importance to refine our understanding of clinically relevant processes. These include vascular remodeling, such as aortic dilation, which is particularly important in some congenital heart defects (CHD). A novel methodological framework for three-dimensional shape analysis has been applied for the first time in a CHD scenario, i.e., bicuspid aortic valve (BAV) disease, the most common CHD. Three-dimensional aortic shapes (n = 94) reconstructed from cardiovascular magnetic resonance imaging (MRI) data as surface meshes represented the input for a longitudinal atlas model, using multiple scans over time (n = 2-4 per patient). This model relies on diffeomorphism transformations in the absence of point-to-point correspondence, and on the right combination of initialization, estimation and registration parameters. We computed the shape trajectory of an average disease progression in our cohort, as well as time-dependent parameters, geometric variations and the average shape of the population. Results cover a spatiotemporal spectrum of visual and numerical information that can be further used to run clinical associations. This proof-of-concept study demonstrates the feasibility of applying advanced statistical shape models to track disease progression and stratify patients with CHD.

The use of 3D-printed models in patient communication: a scoping review.

3D models have been used as an asset in many clinical applications and a variety of disciplines, and yet the available literature studying the use of 3D models in communication is limited. This scoping review has been conducted to draw conclusions on the current evidence and learn from previous studies, using this knowledge to inform future work. Our search strategy revealed 269 papers, 19 of which were selected for final inclusion and analysis. When assessing the use of 3D models in doctor-patient communication, there is a need for larger studies and studies including a long-term follow up. Furthermore, there are forms of communication that are yet to be researched and provide a niche that may be beneficial to explore.

Three-Dimensional Printed Models of the Heart Represent an Opportunity for Inclusive Learning.

Three-dimensional (3D) printed models of anatomic structures offer an alternative to studying manufactured, "idealized" models or cadaveric specimens. The utility of 3D printed models of the heart for clinical veterinary students learning echocardiographic anatomy is unreported. This study aimed to assess the feasibility and utility of 3D printed models of the canine heart as a supplementary teaching aid in final-year vet students. We hypothesized that using 3D printed cardiac models would improve test scores and feedback when compared with a control group. Students (n = 31) were randomized to use either a video guide to echocardiographic anatomy alongside 3D printed models (3DMs) or video only (VO). Prior to a self-directed learning session, students answered eight extended matching questions as a baseline knowledge assessment. They then undertook the learning session and provided feedback (Likert scores and free text). Students repeated the test within 1 to 3 days. Changes in test scores and feedback were compared between 3DM and VO groups, and between track and non-track rotation students. The 3DM group had increased test scores in the non-track subgroup. Track students' test scores in the VO group increased, but not in the 3DM group. Students in the 3DM group had a higher completion rate, and more left free-text feedback. Feedback from 3DM was almost universally positive, and students believed more strongly that these should be used for future veterinary anatomy teaching. In conclusion, these pilot data suggest that 3D printed canine cardiac models are feasible to produce and represent an inclusive learning opportunity, promoting student engagement.

Role of 3D printing technology in paediatric teaching and training: a systematic review.

BACKGROUND: In the UK, undergraduate paediatric training is brief, resulting in trainees with a lower paediatric knowledge base compared with other aspects of medicine. With congenital conditions being successfully treated at childhood, adult clinicians encounter and will need to understand these complex pathologies. Patient-specific 3D printed (3DP) models have been used in clinical training, especially for rarer, complex conditions. We perform a systematic review to evaluate the evidence base in using 3DP models to train paediatricians, surgeons, medical students and nurses. METHODS: Online databases PubMed, Web of Science and Embase were searched between January 2010 and April 2020 using search terms relevant to "paediatrics", "education", "training" and "3D printing". Participants were medical students, postgraduate trainees or clinical staff. Comparative studies (patient-specific 3DP models vs traditional teaching methods) and non-comparative studies were included. Outcomes gauged objective and subjective measures: test scores, time taken to complete tasks, self-reported confidence and personal preferences on 3DP models. If reported, the cost of and time taken to produce the models were noted. RESULTS: From 587 results, 15 studies fit the criteria of the review protocol, with 5/15 being randomised controlled studies and 10/15 focussing on cardiovascular conditions. Participants using 3DP models demonstrated improved test scores and faster times to complete procedures and identify anatomical landmarks compared with traditional teaching methods (2D diagrams, lectures, videos and supervised clinical events). User feedback was positive, reporting greater user self-confidence in understanding concepts with users wishing for integrated use of 3DP in regular teaching. Four studies reported the costs and times of production, which varied depending on model complexity and printer. 3DP models were cheaper than 'off-the-shelf' models available on the market and had the benefit of using real-world pathologies. These mostly non-randomised and single-centred studies did not address bias or report long-term or clinically translatable outcomes. CONCLUSIONS: 3DP models were associated with greater user satisfaction and good short-term educational outcomes, with low-quality evidence. Multicentred, randomised studies with long-term follow-up and clinically assessed outcomes are needed to fully assess their benefits in this setting. PROSPERO REGISTRATION NUMBER: CRD42020179656.

Rapid Prototyping Flexible Aortic Models Aids Sizing of Valve Leaflets and Planning the Ozaki Repair.

Two patients with bicuspid aortic valve were selected for aortic valve repair using the Ozaki procedure. Patient-specific models of their aortic roots were generated based on computed tomography data and were 3-dimensional printed using a flexible resin. The models allowed sizing of the valve leaflets and practicing of leaflet suturing. (Level of Difficulty: Advanced.).

Analysis of Neat Biofluids Obtained During Cardiac Surgery Using Nanoparticle Tracking Analysis: Methodological Considerations.

Small extracellular vesicles (sEVs) are those nanovesicles 30-150 nm in size with a role in cell signalling and potential as biomarkers of disease. Nanoparticle tracking analysis (NTA) techniques are commonly used to measure sEV concentration in biofluids. However, this quantification technique can be susceptible to sample handing and machine settings. Moreover, some classes of lipoproteins are of similar sizes and could therefore confound sEV quantification, particularly in blood-derived preparations, such serum and plasma. Here we have provided methodological information on NTA measurements and systematically investigated potential factors that could interfere with the reliability and repeatability of results obtained when looking at neat biofluids (i.e., human serum and pericardial fluid) obtained from patients undergoing cardiac surgery and from healthy controls. Data suggest that variables that can affect vesicle quantification include the level of contamination from lipoproteins, number of sample freeze/thaw cycles, sample filtration, using saline-based diluents, video length and keeping the number of particles per frame within defined limits. Those parameters that are of less concern include focus, the "Maximum Jump" setting and the number of videos recorded. However, if these settings are clearly inappropriate the results obtained will be spurious. Similarly, good experimental practice suggests that multiple videos should be recorded. In conclusion, NTA is a perfectible, but still commonly used system for sEVs analyses. Provided users handle their samples with a highly robust and consistent protocol, and accurately report these aspects, they can obtain data that could potentially translate into new clinical biomarkers for diagnosis and monitoring of cardiovascular disease.

Use of 3D Models in the Surgical Decision-Making Process in a Case of Double-Outlet Right Ventricle With Multiple Ventricular Septal Defects.

3D printing has recently become an affordable means of producing bespoke models and parts. This has now been extended to models produced from medical imaging, such as computed tomography (CT). Here we report the production of a selection of 3D models to compliment the available imaging data for a 12-month-old child with double-outlet right ventricle and two ventricular septal defects. The models were produced to assist with case management and surgical planning. We used both stereolithography and polyjet techniques to produce white rigid and flexible color models, respectively. The models were discussed both at the joint multidisciplinary meeting and between surgeon and cardiologist. From the blood pool model the clinicians were able to determine that the position of the coronary arteries meant an arterial switch operation was unlikely to be feasible. The soft myocardium model allowed the clinicians to assess the VSD anatomy and relationship with the aorta. The models, therefore, were of benefit in the development of the surgical plan. It was felt that the clinical situation was stable enough that an immediate intervention was not required, but the timing of any intervention would be dictated by decreasing oxygen saturation. Subsequently, the oxygen saturation of the patient did decrease and the decision was made to intervene. A further model was created to demonstrate the tricuspid apparatus. An arterial switch was ultimately performed without the LeCompte maneuver, the muscular VSD enlarged and baffled into the neo aortic root and the perimembranous VSD closed. At 1 month follow up SO2 was 100%, there was no breathlessness and no echocardiogram changes.

Three-dimensional printing in congenital heart disease: Considerations on training and clinical implementation from a teaching session.

In light of growing interest for three-dimensional printing technology in the cardiovascular community, this study focused on exploring the possibilities of providing training for cardiovascular three-dimensional printing in the context of a relevant international congress and providing considerations on the delivery of such courses. As a second objective, the study sought to capture preferences in relation to three-dimensional printing uses and set-ups from those attending the training session. A survey was administered to n = 30 professionals involved or interested in three-dimensional printing cardiovascular models following a specialised teaching session. Survey results suggest the potential for split training sessions, with a broader introduction for those with no prior experience in three-dimensional printing followed by a more in-depth and hands-on session. All participants agreed on the potential of the technology in all its applications, particularly for aiding decision-making around complex surgical or interventional cases. When exploring setting up an in-house three-dimensional printing service, the majority of participants reported that their centre was already equipped with an in-house facility or expressed a desire that such a facility should be available, with a minority preferring consigning models to an external third party for printing.

Three-Dimensional Printing of Fetal Models of Congenital Heart Disease Derived From Microfocus Computed Tomography: A Case Series.

This article presents a case series of n = 21 models of fetal cardiovascular anatomies obtained from post mortem microfocus computed tomography (micro-CT) data. The case series includes a broad range of diagnoses (e.g., tetralogy of Fallot, hypoplastic left heart syndrome, dextrocardia, double outlet right ventricle, atrio-ventricular septal defect) and cases also had a range of associated extra-cardiac malformations (e.g., VACTERL syndrome, central nervous system anomalies, renal anomalies). All cases were successfully reconstructed from the microfocus computed tomography data, demonstrating the feasibility of the technique and of the protocols, including in-house printing with a desktop 3D printer (Form2, Formlabs). All models were printed in 1:1 scale as well as with the 5-fold magnification, to provide insight into the intra-cardiac structures. Possible uses of the models include education and training.

Human Pericardial Fluid Contains Exosomes Enriched with Cardiovascular-Expressed MicroRNAs and Promotes Therapeutic Angiogenesis.

The pericardial fluid (PF) is contained in the pericardial sac surrounding the heart. MicroRNA (miRNA) exchange via exosomes (endogenous nanoparticles) contributes to cell-to-cell communication. We investigated the hypotheses that the PF is enriched with miRNAs secreted by the heart and that it mediates vascular responses through exosome exchange of miRNAs. The study was developed using leftover material from aortic valve surgery. We found that in comparison with peripheral plasma, the PF contains exosomes enriched with miRNAs co-expressed in patients' myocardium and vasculature. At a functional level, PF exosomes improved survival, proliferation, and networking of cultured endothelial cells (ECs) and restored the angiogenic capacity of ECs depleted (via Dicer silencing) of their endogenous miRNA content. Moreover, PF exosomes improved post-ischemic blood flow recovery and angiogenesis in mice. Mechanistically, (1) let-7b-5p is proangiogenic and inhibits its target gene, TGFBR1, in ECs; (2) PF exosomes transfer a functional let-7b-5p to ECs, thus reducing their TGFBR1 expression; and (3) let-7b-5p depletion in PF exosomes impairs the angiogenic response to these nanoparticles. Collectively, our data support the concept that PF exosomes orchestrate vascular repair via miRNA transfer.

Coronary Artery-Bypass-Graft Surgery Increases the Plasma Concentration of Exosomes Carrying a Cargo of Cardiac MicroRNAs: An Example of Exosome Trafficking Out of the Human Heart with Potential for Cardiac Biomarker Discovery.

INTRODUCTION: Exosome nanoparticles carry a composite cargo, including microRNAs (miRs). Cultured cardiovascular cells release miR-containing exosomes. The exosomal trafficking of miRNAs from the heart is largely unexplored. Working on clinical samples from coronary-artery by-pass graft (CABG) surgery, we investigated if: 1) exosomes containing cardiac miRs and hence putatively released by cardiac cells increase in the circulation after surgery; 2) circulating exosomes and exosomal cardiac miRs correlate with cardiac troponin (cTn), the current "gold standard" surrogate biomarker of myocardial damage. METHODS AND RESULTS: The concentration of exosome-sized nanoparticles was determined in serial plasma samples. Cardiac-expressed (miR-1, miR-24, miR-133a/b, miR-208a/b, miR-210), non-cardiovascular (miR-122) and quality control miRs were measured in whole plasma and in plasma exosomes. Linear regression analyses were employed to establish the extent to which the circulating individual miRs, exosomes and exosomal cardiac miR correlated with cTn-I. Cardiac-expressed miRs and the nanoparticle number increased in the plasma on completion of surgery for up to 48 hours. The exosomal concentration of cardiac miRs also increased after CABG. Cardiac miRs in the whole plasma did not correlate significantly with cTn-I. By contrast cTn-I was positively correlated with the plasma exosome level and the exosomal cardiac miRs. CONCLUSIONS: The plasma concentrations of exosomes and their cargo of cardiac miRs increased in patients undergoing CABG and were positively correlated with hs-cTnI. These data provide evidence that CABG induces the trafficking of exosomes from the heart to the peripheral circulation. Future studies are necessary to investigate the potential of circulating exosomes as clinical biomarkers in cardiac patients.

Exosomes and exosomal miRNAs in cardiovascular protection and repair.

Cell-cell communication between cardiac and vascular cells and from stem and progenitor cells to differentiated cardiovascular cells is both an important and complex process, achieved through a diversity of mechanisms that have an impact on cardiovascular biology, disease and therapeutics. In recent years, evidence has accumulated suggesting that extracellular vesicles (EVs) are a new system of intercellular communication. EVs of different sizes are produced via different biogenesis pathways and have been shown to be released and taken up by most of known cell types, including heart and vascular cells, and stem and progenitor cells. This review will focus on exosomes, the smallest EVs (up to 100nm in diameter) identified so far. Cells can package cargoes consisting of selective lipids, proteins and RNA in exosomes and such cargoes can be shipped to recipient cells, inducing expressional and functional changes. This review focuses on exosomes and microRNAs in the context of cardiovascular disease and repair. We will describe exosome biogenesis and cargo formation and discuss the available information on in vitro and in vivo exosomes-based cell-to-cell communication relevant to cardiovascular science. The methods used in exosome research will be also described. Finally, we will address the promise of exosomes as clinical biomarkers and their impact as a biomedical tool in stem cell-based cardiovascular therapeutics.

Bcl-x inactivation in macrophages accelerates progression of advanced atherosclerotic lesions in Apoe(-/-) mice.

OBJECTIVE: Bcl-x is the most abundantly expressed member of the Bcl-2 gene family in macrophages, but its role in macrophage apoptosis during atherogenesis is unknown. METHODS AND RESULTS: We previously reported dual pro- and antiatherogenic effects of macrophage survival in early versus advanced atherosclerotic lesions, respectively, potentially reflecting growing impairment of efferocytosis during plaque progression. Here, we specifically inactivated Bcl-x in macrophages and evaluated its impact on atherosclerotic lesion formation in Apoe(-/-) mice at various stages of the disease. Bcl-x deficiency in macrophages increased their susceptibility to apoptosis, resulting in the depletion of tissue macrophages in vivo, including its major pool, Küppfer cells in the liver. We also observed increased cholesterol levels that were, however, not associated with any acceleration of early atherosclerotic plaque progression. This observation suggests that the atheroprotective effect of macrophage apoptosis at that stage of disease was counterbalanced by enhanced cholesterol levels. Bcl-x KO(mac)/Apoe(-/-) mice exhibited significantly larger advanced lesions than control mice. These lesions showed vulnerable traits. Such enhanced lesion size may occur as a result not only of apoptotic cell accumulation but also of elevated cholesterol levels. CONCLUSIONS: Modulation of macrophage resistance to apoptosis through targeted deletion of Bcl-x has a major impact on the entire macrophage cell population in the body, including Küpffer cells. Macrophage survival may, therefore, not only influence atherosclerotic plaque development and vulnerability but also cholesterol metabolism.