3D Heart Research Articles

LivHeart: A Multi Organ‐on‐Chip Platform to Study Off‐Target Cardiotoxicity of Drugs Upon Liver Metabolism

AbstractThe drug discovery and development process is still long, costly, and highly risky. The principal attrition factor is undetected toxicity, with hepatic and cardiac toxicities playing a critical role and being the main responsible of safety‐related drug withdrawals from the market. Multi Organs‐on‐Chip (MOoC) represent a disruptive solution to study drug‐related effects on several organs simultaneously and to efficiently predict drug toxicity in preclinical trials. Specifically focusing on drug safety, different technological features are applied here to develop versatile MOoC platforms encompassing two culture chambers for generating and controlling the type of communication between a metabolically competent liver model and a functional 3D heart model. The administration of the drug Terfenadine, a cardiotoxic compound liver‐metabolized into the noncardiotoxic Fexofenadine, proves that liver metabolism and a fine control over drug diffusion are fundamental to elicit a physio‐pathological cardiac response. From these results, an optimized LivHeart platform is developed to house a liver model and a cardiac construct that can be mechanically trained to achieve a beating microtissue, whose electrophysiology can be directly recorded in vitro. The platform is proved able to predict off‐target cardiotoxicity of Terfenadine after liver metabolism both in terms of cell viability and functionality.

Three-Dimensional-Enabled Surgical Planning for the Correction of Right Partial Anomalous Pulmonary Venous Return.

Objectives: The surgical technique for right partial anomalous pulmonary venous return (PAPVR) depends on the location of the anomalous pulmonary veins (PVs). With this in mind, we sought to evaluate the impact of 3D heart segmentation and reconstruction on preoperative surgical planning. Methods: A retrospective study was conducted on all patients who underwent PAPVR repair at our institution between January 2018 and October 2021; three-dimensional segmentations and reconstructions of all the heart anatomies were performed. A score (the PAPVR score) was established and calculated using two anatomical parameters (the distance between the most cranial anomalous PV and the superior rim of the sinus venosus defect/the sum of the latter and the distance between the PV and the azygos vein) to predict the type of correction. Results: A total of 30 patients were included in the study. The PAPVR score was found to be a good predictor of the type of surgery performed. A value > 0.68 was significantly associated with a Warden procedure (p < 0.001) versus single/double patch repair. Conclusions: Three-dimensional heart segmentations and reconstructions improve the quality of surgical planning in the case of PAPVR and allow for the introduction of a score that may facilitate surgical decisions on the type of repair required.

Utility of three-dimensional virtual and printed models for veterinary student education in congenital heart disease

Introduction: Congenital heart disease (CHD) is a common heart defect that can be present in small and large animals at birth. Student understanding of normal and abnormal cardiac anatomy is imperative for proper diagnosis and management of CHD. Objectives were to create and use three-dimensional (3D) heart models during a workshop to understand veterinary student perception of 3D models for CHD education. We hypothesized that 3D models would enhance student understanding of CHD, and students would prefer 3D models during cardiac education. Materials and Methods: Computed tomography angiography datasets from canine patent ductus arteriosus were used to create 3D models. Segmentation and computer-aided design were performed. Virtual overlays of 3D models were displayed onto two-dimensional (2D) thoracic radiographs. Stereolithography files were fabricated by a 3D printer. Students participated in a CHD workshop consisting of 2D and 3D teaching stations. Self-assessment surveys before and after the workshop were completed. Results: Twenty-two veterinary students attended the workshop. The 3D-printed models were found to be the most helpful teaching modality based on students’ perception. The 3D-printed model (P < 0.0001) and the 3D digital model (P < 0.0001) were perceived to be significantly more helpful than the 2D radiograph station. All students strongly agreed (15/22) or agreed (7/22) that virtual models overlayed onto 2D radiographs enhanced their spatial recognition of anatomic structures. All students strongly agreed (17/22) and agreed (5/22) that the CHD workshop was a valuable learning opportunity. Conclusion: Creation of virtual and fabricated 3D heart models is feasible. Three-dimensional models may be helpful when understanding spatial recognition of cardiovascular anatomy on thoracic radiographs. We advocate using 3D heart models during CHD education.

Weakly supervised inference of personalized heart meshes based on echocardiography videos.

Echocardiography provides recordings of the heart chamber size and function and is a central tool for non-invasive diagnosis of heart diseases. It produces high-dimensional video data with substantial stochasticity in the measurements, which frequently prove difficult to interpret. To address this challenge, we propose an automated framework to enable the inference of a high resolution personalized 4D (3D plus time) surface mesh of the cardiac structures from 2D echocardiography video data. Inferring such shape models arises as a key step towards accurate personalized simulation that enables an automated assessment of the cardiac chamber morphology and function. The proposed method is trained using only unpaired echocardiography and heart mesh videos to find a mapping between these distinct visual domains in a self-supervised manner. The resulting model produces personalized 4D heart meshes, which exhibit a high correspondence with the input echocardiography videos. Furthermore, the 4D heart meshes enable the automatic extraction of echocardiographic variables, such as ejection fraction, myocardial muscle mass, and volumetric changes of chamber volumes over time with high temporal resolution.

Three-Dimensional Heart Segmentation and Absolute Quantitation of Cardiac 123I-metaiodobenzylguanidine Sympathetic Imaging Using SPECT/CT.

Background: A three-dimensional (3D) approach to absolute quantitation of 123I-metaiodobenzylguanidine (MIBG) sympathetic nerve imaging using single-photon emission tomography (SPECT) / computed tomography (CT) is not available. Therefore, we calculated absolute cardiac counts and standardized uptake values (SUVs) from images of 72 consecutive patients with cardiac and neurological diseases using 123I-MIBG SPECT/CT and compared them with conventional planar quantitation. We aimed to develop new methods for 3D heart segmentation and the quantitation of these diseases. Methods: We manually segmented early and late SPECT/CT images of the heart in 3D, then calculated mean (SUVmean) and maximum (SUVmax) SUVs. We analyzed correlations between SUVs and planar heart-to-mediastinum ratios (HMRs), and between washout rates (WRs) derived from the SUVs and planar data. We also categorized WRs as normal or abnormal using linear regression lines determined by the relationship between SPECT/CT and planar WRs, and assessed agreement between them. Results: We calculated SUVmean and SUVmax from all early and late 123I-MIBG SPECT/CT images. Planar HMRs correlated with early and late SUVmean (R2=0.59 and 0.73, respectively) and SUVmax (R2=0.46 and 0.60, respectively; both p<0.0001). The SPECT/CT WRs determined based on SUVmean and SUVmax (R2=0.79 and 0.45, p<0.0001) closely correlated with planar WRs. Agreement of high and low WRs between planar WRs and SPECT/CT WRs calculated using SUVmax and SUVmean reached 88.1% and 94.4% respectively. Conclusions: We found that sympathetic nervous activity could be absolutely quantified in 3D from 123I-MIBG SPECT/CT images. Therefore, we propose a new method for quantifying sympathetic innervation on SPECT/CT images.

A 3D-printed surgical guide for ischemic scar targeting and ablation.

3D printing technology development in medical fields allows to create 3D models to assist preoperative planning and support surgical procedures. Cardiac ischemic scar is clinically associated with malignant arrhythmias. Catheter ablation is aimed at eliminating the arrhythmogenic tissue until the sinus rhythm is restored. The scope of this work is to describe the workflow for a 3D surgical guide able to define the ischemic scar and target catheter ablation. For the patient-specific 3D surgical guide and 3D heart phantom model realization, both CT scan and cardiac MRI images were processed; this was necessary to extract anatomical structures and pathological information, respectively. Medical images were uploaded and processed in 3D Slicer. For the surgical guide modeling, images from CT scan and MRI were loaded in Meshmixer and merged. For the heart phantom realization, only the CT segmentation was loaded in Meshmixer. The surgical guide was printed in MED625FLX with Polyjet technology. The heart phantom was printed in polylactide with FDM technology. 3D-printed surgical model was in agreement with prespecified imputed measurements. The phantom fitting test showed high accuracy of the 3D surgical tool compared with the patient-specific reproduced heart. Anatomical references in the surgical guide ensured good stability. Ablation catheter fitting test showed high suitability of the guide for different ablation tools. A 3D-printed guide for ventricular tachycardia ablation is feasible and accurate in terms of measurements, stability, and geometrical structure. Concerning clinical use, further clinical investigations are eagerly awaited.

Development of a 3D printed surgical guide for Brugada syndrome substrate ablation.

Brugada syndrome (BrS) is a disease associated with ventricular arrhythmias and sudden cardiac death. Epicardial ablation has demonstrated high therapeutic efficacy in preventing ventricular arrhythmias. The purpose of this research is to define a workflow to create a patient-specific 3D-printed tool to be used as a surgical guide for epicardial ablation in BrS. Due to their mechanical properties and biocompatibility, the MED625FLX and TPU95A were used for cardiac 3D surgical guide printing. ECG imaging was used to define the target region on the right ventricular outflow tract (RVOT). CT scan imaging was used to design the model based on patient anatomy. A 3D patient-specific heart phantom was also printed for fitting test. Sterilization test was finally performed. 3D printed surgical models with both TPU95A and MED625FLX models were in agreement with pre-specified imputed measurements. The phantom test showed retention of shape and correct fitting of the surgical tool to the reproduced phantom anatomy, as expected, for both materials. The surgical guide adapted to both the RVOT and the left anterior descending artery. Two of the 3D models produced in MED265FLX showed damage due to the sterilization process. A 3D printed patient-specific surgical guide for epicardial substrate ablation in BrS is feasible if a specific workflow is followed. The design of the 3D surgical guide ensures proper fitting on the heart phantom with good stability. Further investigations for clinical use are eagerly awaited.

Inter-fraction heart displacement during voluntary deep inspiration breath hold radiation therapy without visual feedback measured by daily CBCT.

Purpose/ObjectiveDeep Inspiration Breath Hold (DIBH) is now considered as the standard of care for many breast cancer patients. However, there are still uncertainties about the dose given to the heart, and it is unknown if patients may improve voluntary DIBH depth by gaining experience during treatment. In this study, we will examine the interfractional three-dimensional (3D) heart displacement throughout voluntary DIBH (vDIBH) radiotherapy by means of daily cone-beam computed tomography (CBCT).Material and methodsTwo hundred twenty-five unique CBCTs from 15 patients treated in 15 fractions were analyzed. During CBCT, a vDIBH was conducted without any visual feedback. Patients performed their DIBH freely after receiving explanations and training. After daily CBCT matching to the chest wall (CW), surface-guided radiation therapy (SGRT) tracked DIBH depth to ensure that the CW position was the same as the daily acquired CBCT. The CBCTs were retrospectively registered to the DIBH planning-CT to calculate daily changes in heart displacement relative to the CW.ResultsThe mean displacement of the heart during DIBH treatment relative to the DIBH planning-CT was as follows: 1.1 mm to the right, interquartile range (IQR) 8.0; 0.5 mm superiorly, IQR 4.8; and 0 mm posteriorly, IQR 6.4. The Spearman correlation coefficients (rs) were -0.15 (p=0.025), 0.04 (p=0.549), and 0.03 (p=0.612) for the X, Y, and Z directions, respectively. The differences in median heart displacement were significant: Friedmann rank sum test p=0.031 and pairwise comparison using the Wilcoxon rank-sum test were p=0.008 for X and Y; p=0.33 for X and Z; and p=0.07 for Y and Z. The total median heart motion was δtot median= 7.26 mm, IQR= 6.86 mm.ConclusionDuring DIBH, clinicians must be aware of the wide range of intra- and inter-individual heart position variations. The inter-individual heterogeneity shown in our study should be investigated further in order to avoid unexpected cardiac overexposure and to develop a more accurate heart dose-volume model.

Accelerating cardiovascular research: recent advances in translational 2D and 3D heart models.

In vitro modelling the complex (patho-) physiological conditions of the heart is a major challenge in cardiovascular research. In recent years, methods based on three-dimensional (3D) cultivation approaches have steadily evolved to overcome the major limitations of conventional adherent two-dimensional (2D) monolayer cultivation. These 3D approaches aim to study, reproduce or modify fundamental native features of the heart such as tissue organization and cardiovascular microenvironment. Therefore, these systems have great potential for (patient-specific) disease research, for the development of new drug screening platforms, and for the use in regenerative and replacement therapy applications. Consequently, continuous improvement and adaptation is required with respect to fundamental limitations such as cardiomyocyte maturation, scalability, heterogeneity, vascularization, and reproduction of native properties. In this review, 2D monolayer culturing and the 3D in vitro systems of cardiac spheroids, organoids, engineered cardiac microtissue and bioprinting as well as the ex vivo technique of myocardial slicing are introduced with their basic concepts, advantages, and limitations. Furthermore, recent advances of various new approaches aiming to extend as well as to optimize these in vitro and ex vivo systems are presented.

Ginsenoside Rd ameliorates aflatoxin B1 induced apoptosis via governing antioxidative activity in H9C2 cells and 3D heart spheroids

Aflatoxin B1 exerts potent toxic effects on a variety of tissues or organs in the body; it often contaminates the environment and foods, and thus poses a heavy burden on public health and food safety efforts. As an essential botanical medicine, Ginsenoside Rd has been demonstrated to alleviate multiple organ injuries induced by a variety of toxins. Our study aimed to examine how AFB1 influenced heart cell apoptosis in vitro and determine regulatory effects of Rd in the effects of AFB1 on heart function. For this purpose, the H9C2 cell line and 3D primary heart spheroids were used. RT-qPCR was used to measure apoptosis-related genes’ expression levels. siRNA-based gene knockdown was used for mechanistic analyses. The results revealed that AFB1 potently promoted apoptosis-related genes’ (such as caspase-3/9 genes) expression levels in both H9C2 cells and 3D heart spheroids. Rd alleviated AFB1-induced heart cell apoptosis. Oxidative stress induced by H2O2 potently induced heart cell apoptosis. Rd also significantly reduced superoxide dismutase activity in heart spheroids. Finally, it was suggested that attenuation of Rd against AFB1-caused apoptosis of heart cells were mediated through the induction of antioxidant activity. On the whole, the present study provides useful information which may aid in the development of novel antidotes against toxins and their negative effects, including AFB1-induced heart injury.

Transcatheter closure of inferior sinus venosus defect using a patent ductus arteriosus occluder following simulation with a 3D-printed model.

BackgroundTranscatheter closure of inferior sinus venosus defect (ISVD) is still contraindication. To explore whether transcatheter closure with patent ductus arteriosus (PDA) occluders is possible for ISVD.MethodsFrom June 2014 to March 2021, 12 patients were recruited diagnosed as <25 mm ISVD. The three-dimensional printing (3DP) heart model was produced based on multi-slice computed tomography (MSCT) scans. Preoperative closure simulation was planned on the personalized 3D model for each patient. Follow-up including electrocardiography (ECG), transthoracic echocardiography (TTE), and X-ray was traced.Results3DP models of 12 patients were successfully printed. Twelve patients had been diagnosed with <25 mm ISVD and 4 of them had another secundum atrial septal defect (ASD). All patients were produced interventional therapy successfully. PDA occluder was implanted to closed ISVD, and ASD was closed using ASD occluder simultaneously. The average diameter of ISVD measured by TTE was (12.67±3.80), and the average diameter of sagittal axes and longitudinal axes measured by the 3D-printed model was (17.08±3.20) and (18.42±4.62) mm, respectively. The average size of PDA (diameter of pulmonary artery side) was (28.17±3.35) mm. Compared with the preoperative, the X-ray cardiothoracic ratio (0.51±0.04 vs. 0.47±0.06, P=0.007) and the right ventricle anterior-posterior diameter (31.17±5.65 vs. 24.58±3.75 mm, P<0.001) of postoperative was significantly decreased. During the average (47.75±27.52) months follow-up, it has achieved satisfying results, and there were no severe adverse events such as device transposition, death, and pericardial tamponade occurred.ConclusionsAssisting by 3D heart model, transcatheter closure of ISVD with PDA occluder had an excellent outcome. This method provides a new considerable treatment strategy for ISVD.

Real-Time Echocardiography-Fluoroscopy Fusion Imaging With Automated 3D Heart Segmentation During Transcatheter Structural HeartInterventions.

Real-Time Echocardiography-Fluoroscopy Fusion Imaging With Automated 3D Heart Segmentation During Transcatheter Structural HeartInterventions.

Transcatheter Pulmonary Valve Replacement from Autologous Pericardium with a Self-Expandable Nitinol Stent in an Adult Sheep Model.

Transcatheter pulmonary valve replacement has been established as a viable alternative approach for patients suffering from right ventricular outflow tract or bioprosthetic valve dysfunction, with excellent early and late clinical outcomes. However, clinical challenges such as stented heart valve deterioration, coronary occlusion, endocarditis, and other complications must be addressed for lifetime application, particularly in pediatric patients. To facilitate the development of a lifelong solution for patients, transcatheter autologous pulmonary valve replacement was performed in an adult sheep model. The autologous pericardium was harvested from the sheep via left anterolateral minithoracotomy under general anesthesia with ventilation. The pericardium was placed on a 3D shaping heart valve model for non-toxic cross-linking for 2 days and 21 h. Intracardiac echocardiography (ICE) and angiography were performed to assess the position, morphology, function, and dimensions of the native pulmonary valve (NPV). After trimming, the crosslinked pericardium was sewn onto a self-expandable Nitinol stent and crimped into a self-designed delivery system. The autologous pulmonary valve (APV) was implanted at the NPV position via left jugular vein catheterization. ICE and angiography were repeated to evaluate the position, morphology, function, and dimensions of the APV. An APV was successfully implanted insheep J. In this paper, sheep J was selected to obtain representative results. A 30 mm APV with a Nitinol stent was accurately implanted at the NPV position without any significant hemodynamic change. There was no paravalvular leak, no new pulmonary valve insufficiency, or stented pulmonary valve migration. This study demonstrated the feasibility and safety, in a long-time follow-up, of developing an APV for implantation at the NPV position with a self-expandable Nitinol stent via jugular vein catheterization in an adult sheep model.

Magnetization Transfer BOOST Noncontrast Angiography Improves Pulmonary Vein Imaging in Adults With Congenital Heart Disease.

Cardiac MRI plays an important role in the diagnosis and follow-up of patients with congenital heart disease (CHD). Gadolinium-based contrast agents are often needed to overcome flow-related and off-resonance artifacts that can impair the quality of conventional noncontrast 3D imaging. As serial imaging is often required in CHD, the development of robust noncontrast 3D MRI techniques is desirable. To assess the clinical utility of noncontrast enhanced magnetization transfer and inversion recovery prepared 3D free-breathing sequence (MTC-BOOST) compared to conventional 3D whole heart imaging in patients with CHD. Prospective, image quality. A total of 27 adult patients (44% female, mean age 30.9 ± 14.8 years) with CHD. A 1.5 T; free-breathing 3D MTC-BOOST sequence. MTC-BOOST was compared to diaphragmatic navigator-gated, noncontrast T2 prepared 3D whole-heart imaging sequence (T2prep-3DWH) for comparison of vessel dimensions, lumen-to-myocardium contrast ratio (CR), and image quality (vessel wall sharpness and presence and type of artifacts) assessed by two experienced cardiologists on a 5-point scale. Mann-Whitney test, paired Wilcoxon signed-rank test, Bland-Altman plots. P < 0.05 was considered statistically significant. MTC-BOOST significantly improved image quality and CR of the right-sided pulmonary veins (PV): (CR: right upper PV 1.06 ± 0.50 vs. 0.58 ± 0.74; right lower PV 1.32 ± 0.38 vs. 0.81 ± 0.73) compared to conventional T2prep-3DWH imaging where the PVs were not visualized in some cases due to off-resonance effects. MTC-BOOST demonstrated resistance to degradation of luminal signal (assessed by CR) secondary to accelerated or turbulent flow conditions. T2prep-3DWH had higher image quality scores than MTC-BOOST for the aorta and coronary arteries; however, great vessel dimensions derived from MTC-BOOST showed excellent agreement with standard T2prep-3DWH imaging. MTC-BOOST allows for improved contrast-free imaging of pulmonary veins and regions characterized by accelerated or turbulent blood flow compared to standard T2prep-3DWH imaging, with excellent agreement of great vessel dimensions. 1 TECHNICAL EFFICACY: Stage 2.

High-Resolution 3D Heart Models of Cardiomyocyte Subpopulations in Cleared Murine Heart.

Biological tissues are naturally three-dimensional (3D) opaque structures, which poses a major challenge for the deep imaging of spatial distribution and localization of specific cell types in organs in biomedical research. Here we present a 3D heart imaging reconstruction approach by combining an improved heart tissue-clearing technique with high-resolution light-sheet fluorescence microscopy (LSFM). We have conducted a three-dimensional and multi-scale volumetric imaging of the ultra-thin planes of murine hearts for up to 2,000 images per heart in x-, y-, and z three directions. High-resolution 3D volume heart models were constructed in real-time by the Zeiss Zen program. By using such an approach, we investigated detailed three-dimensional spatial distributions of two specific cardiomyocyte populations including HCN4 expressing pacemaker cells and Pnmt+ cell-derived cardiomyocytes by using reporter mouse lines Hcn4DreER/tdTomato and PnmtCre/ChR2−tdTomato. HCN4 is distributed throughout right atrial nodal regions (i.e., sinoatrial and atrioventricular nodes) and the superior-inferior vena cava axis, while Pnmt+ cell-derived cardiomyocytes show distinct ventral, left heart, and dorsal side distribution pattern. Our further electrophysiological analysis indicates that Pnmt + cell-derived cardiomyocytes rich left ventricular (LV) base is more susceptible to ventricular arrhythmia under adrenergic stress than left ventricular apex or right ventricle regions. Thus, our 3D heart imaging reconstruction approach provides a new solution for studying the geometrical, topological, and physiological characteristics of specific cell types in organs.

Aortic dilatation using cardiac magnetic resonance in asymptomatic ELITE athletes

Abstract Funding Acknowledgements Type of funding sources: None. Purpose Aortic dilatation is associated with acute aortic pathology. Cardiac magnetic resonance (CMR) data in asymptomatic elite athletes is lacking. Therefore, we investigated the prevalence of aortic dilatation in a cohort of elite-level athletes using CMR. Methods We performed a cross-sectional study of aortic dimensions among elite-level (national-, international-, Olympic-, Paralympic-level or comparable) athletes. All athletes were asymptomatic and examined during pre-participation screening. Each underwent CMR with 3D whole heart in diastole (1.5 mm voxel) for aortic measurements, next to cine imaging, late gadolinium enhancement (LGE), and T1-mapping. We defined dilatation as 38 and 40 mm at the aortic root (sinus of Valsalva cusp-cusp), 27 and 31 mm at the sinotubular junction, and 23 and 26 mm at the level of the diaphragm, in male- and female athletes, respectively. Athletes were grouped for having 0- (normal), 1-, 2- or 3 measurements above cut-off values. Results We screened 156 athletes, 41% female, with a mean age (±SD) of 28±7 and body surface area (BSA) of 2.0±0.2 m2. Mean aortic dimensions were 33±4 mm for the sinus of Valsalva, 28±3 mm for the sinotubular junction, 20±3 mm for the aorta at diaphragm. We observed indexed end-diastolic volumes (EDVi) of 122±20 and 123±20 ml/m2, indexed end-systolic volumes (ESVi) of 53±13 and 54±16 ml/m2, stroke volumes (SV) of 129±36 and 126±39 ml, and ejection fractions (EF) of 56±5 and 55±6 %, in the left- (LV) and right ventricle (RV), respectively Fifty-three (34%) athletes, of which 45% female, had 1 or 2 aortic measurements above conventional cut-off values (Table 1). Eleven (7%), 18% female, had 2 aortic measurements above cut-off values. No athlete had all 3 measurements above cut-offs values. Athletes with 2 dilated measurements compared to athletes with 1 or 0 dilated measurements, had greater LV EDVi (145±19 vs. 119±18 vs. 120±19 ml/m2, p&amp;lt;0.001), greater RV EDVi (142±18 vs. 119±17 vs. and 122±20 ml/m2, p=0.002), greater LV ESVi (66±10 vs. 51±13 vs. 52±13 ml/m2, p=0.002), greater RV ESVi (66±10 vs. 53±13 vs. 53±17 ml/m2, p=0.039), greater LV SV (156±26 vs. 132±35 vs. 125±36 ml, p=0.020), and greater RV SV (152±25 vs. 130±34 vs. 121±41 ml, p=0.031), 2- vs, 1- vs. 0 dilated segments, respectively (Table 1, Figure 1). Athletes with dilated measurements had no LGE (excluding the hinge point), no difference in T1-mapping times, or LV- and RV EF, compared to athletes without dilated measurements. Conclusion One in three elite-athletes has dilatation in one or more aortic segments, including the sinus of Valsalva, sinotubular junction, or the aorta at diaphragm. Athletes with 2 dilated measurements (7%) had greater LV- and RV EDVi, ESVi, and SV, suggesting an association with ventricular volumes. Our findings in asymptomatic elite athletes, with normal EF and no LGE and comparable T1-mapping times, could be a sign of an outspoken physiological sports adaptation, instead of pathology.

3D Embryonic Heart Goes Mobile: Efficacy of Mobile Application in Congenital Cardiac Embryology Education

Mastery of embryonic heart development is challenging but critical for medical professionals due to the frequency and variety of congenital cardiac defects that arise when the process goes awry. Unfortunately, teaching and learning cardiac embryology is difficult due to a lack of accurate and effective visual resources that depict this complex spatiotemporal event. To that end, an interactive mobile application named Embryonic Virtual Heart Application (EVHA) was developed as an accessible and interactive learner platform featuring a set of anatomically accurate 3D embryonic heart models with and without congenital cardiac defects (Figure 1). The project aims to assess whether the EVHA usage leads to measurable learning outcomes for first‐year medical students in the absence of a traditional lecture on cardiac embryology and congenital cardiac defects.In a COMIRB exempt study (#21‐4827), as a part of an optional pre‐work activity prior to the cardiac embryology class, 172 first‐year medical students were given access to a pre‐quiz (Q1) on cardiac embryology before interacting with the EVHA. After the EVHA usage, a post‐quiz (Q2) comprised of a set of matched, but different, questions than the Q1 was provided. During the class, students’ retention on this topic was assessed by a set of clinically oriented questions (Q3). Lastly, students completed an optional survey on their perceived value of the EVHA after the class. The learning outcomes from the EVHA usage were assessed by a one‐way ANOVA to compare Q1, Q2, and Q3 performances. To analyze the survey results, the frequency of each Likert scale score was averaged while thematic analysis was performed on the comments.The learning outcomes analysis revealed a significant increase in quiz performance between Q1 (22% ± 19%) and Q2 (65% ± 24%) with a 43% increase in the score (p&lt;0.001; d=0.7; n=21). In‐class performance (Q3) average (61%; n=61) for all participants was not significantly different from Q2 (p&gt;0.05), however those students who completed all optional prework (Q1, EVHA, Q2) had a significantly higher Q3 performance (79%; p &lt;0.05; n=9). Survey analysis indicates that students perceive EVHA as an effective learning tool with its greatest strength being the interactive 3D virtual models of the congenital cardiac defects.Despite the limitations and confounds in this project, these results indicate that the EVHA may be an effective tool contributing to significant learning outcomes independent from a formal class and can further enhance learning in the classroom and on higher‐order assessments. The impact of this project is its contribution of an accessible, portable and visually‐oriented learning resource on cardiac embryology with clinical emphasis. Based on the learning outcomes data, the project also demonstrates the potential of educational mobile applications in medical curricula in which contact hours are limited.

Topographical Mapping of Catecholaminergic Axon Distribution and Morphology in the Flat‐Mounts of the Mouse Heart

The sympathetic nervous system plays a crucial role in the control of heart functions. However, the distribution and morphology of sympathetic postganglionic innervation of the heart has not been well elucidated, which has significantly impeded the understanding of the sympathetic neuroanatomical organization and control of the heart. Our goal is to provide a map of the topographical innervation of sympathetic postganglionic neurons in the whole heart of mice. In this study, we used Tyrosine hydroxylase (TH) as a marker for sympathetic axons and applied a combination of state‐of‐the‐art techniques, including confocal microscopy, Zeiss Imager microscopy, flat‐mount tissue processing and immunohistochemistry, Neurolucida 360 Tracing and integration of the tracing data onto a 3D heart scaffold. We found that 1) Multiple large extrinsic TH‐IR nerve bundles entered the heart and branched out into smaller axons which covered the whole left and right atria and ventricles, 2) These TH‐IR bundles branched out into smaller axon bundles and ramified into individual axons covering the whole left and right atria and ventricles. 3) The TH‐IR axons formed an extensive neural network in the epicardium and axons formed varicose synaptic endings within the cardiac muscle. 4) TH‐IR axons and terminals were densest in the sinoatrial (SA) and atrioventricular (AV) node regions. 5) TH‐IR axons innervated blood vessels and fat cells. 6) Many principal neurons in intrinsic cardiac ganglia and small intensely fluorescent (SIF) cells were TH‐IR. 7) However, TH‐IR axons do not appear to innervate any cardiac principal neurons and SIF cells. 8) TH‐IR axon innervation will be integrated into a 3D scaffold. Our work will provide a comprehensive topographical map of the catecholaminergic efferent axon distribution, innervation, and morphology of the whole heart at single cell/axon/synapse scale that will be used to create a cardiac sympathetic‐brain atlas. It will also provide an anatomical reference to evaluate the altered sympathetic cardiac control in pathological conditions. The first two authors contributed equally to this work.

3D-printed heart models for hands-on training in pediatric cardiology – the future of modern learning and teaching?

Background: This project aims to develop a new concept in training pediatric cardiologists to meet the requirements of interventional cardiac catheterizations today in terms of complexity and importance. This newly developed hands-on training program is supposed to enable the acquisition of certain skills which are necessary when investigating and treating patients in a catheter laboratory.Methods: Based on anonymous CT-scans of pediatric patients’ digital 3D heart models with or without cardiac defects were developed and printed three-dimensionally in a flexible material visible under X-ray. Hands-on training courses were offered using models of a healthy heart and the most common congenital heart defects (CHD). An evaluation was performed by quantifying fluoroscopy times (FL-time) and a questionnaire.Results: The acceptance of theoretical and practical contents within the hands-on training was very positive. It was demonstrated that it is possible to master various steps of a diagnostic procedure and an intervention as well as to practice and repeat them independently which significantly reduced FL-time. The participants stated that the hands-on training led to more confidence in interventions on real patients.Conclusion: With the development of a training module using 3D-printed heart models, basic and advanced training in the field of diagnostic cardiac examinations as well as interventional therapies of CHD is possible. The learning effect for both, practical skills and theoretical understanding, was significant which underlines the importance of integrating such hands-on trainings on 3D heart models in education and practical training.

Contractility analysis of human engineered 3D heart tissues by an automatic tracking technique using a standalone application.

The use of Engineered Heart Tissues (EHT) as in vitro model for disease modeling and drug screening has increased, as they provide important insight into the genetic mechanisms, cardiac toxicity or drug responses. Consequently, this has highlighted the need for a standardized, unbiased, robust and automatic way to analyze hallmark physiological features of EHTs. In this study we described and validated a standalone application to analyze physiological features of EHTs in an automatic, robust, and unbiased way, using low computational time. The standalone application “EHT Analysis” contains two analysis modes (automatic and manual) to analyzes the contractile properties and the contraction kinetics of EHTs from high speed bright field videos. As output data, the graphs of displacement, contraction force and contraction kinetics per file will be generated together with the raw data. Additionally, it also generates a summary file containing all the data from the analyzed files, which facilitates and speeds up the post analysis. From our study we highlight the importance of analyzing the axial stress which is the force per surface area (μN/mm2). This allows to have a readout overtime of tissue compaction, axial stress and leave the option to calculate at the end point of an experiment the physiological cross-section area (PSCA). We demonstrated the utility of this tool by analyzing contractile properties and compaction over time of EHTs made out of a double reporter human pluripotent stem cell (hPSC) line (NKX2.5EGFP/+-COUP-TFIImCherry/+) and different ratios of human adult cardiac fibroblasts (HCF). Our standalone application “EHT Analysis” can be applied for different studies where the physiological features of EHTs needs to be analyzed under the effect of a drug compound or in a disease model.