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Background The Long-ter M O U tcomes after the Multisystem Inflammatory S yndrome I n C hildren (MUSIC) study aims to characterize the frequency and time course of acute and long-term cardiac and non-cardiac sequelae in multisystem inflammatory syndrome in children associated with COVID-19 (MIS-C), which are currently poorly understood. Methods This multicenter observational cohort study will enroll at least 600 patients Conclusion The MUSIC study, with the largest cohort of MIS-C patients and the longest follow-up period to date, will make an important contribution to our understanding of the acute cardiac and non-cardiac manifestations of MIS-C and the long-term effects of this public health emergency.

In patients with interrupted aortic arch and ventricular septal defect (VSD) with a small left ventricular outflow tract (LVOT), either aortopulmonary amalgamation or a Ross-Konno type procedure can be performed to create stable systemic outflow. We sought to analyze factors associated with these different surgical approaches.We retrospectively identified patients who underwent surgical repair for interrupted aortic arch/VSD at our institution between 1998 and 2017. Of these, 43 patients had a small, native LVOT that was unsuitable for systemic outflow. Patient data were retrospectively collected for this cohort and analyzed.Aortopulmonary amalgamation was performed at 7 days (interquartile range [IQR], 5-10) in 30 patients (group I). Within group I a primary Yasui repair with ventricular septation was performed in 3 patients and a Norwood-type repair in the other 27. Of these 27, 19 underwent subsequent biventricular conversion at 9 months (IQR, 7-11). In contrast 13 patients underwent a Ross procedure at 12 days (IQR, 6-27) (group II). Compared with group I, group II patients had a smaller VSD (3.5 vs 5.1 mm, P.001) that was more often remote from the semilunar valves (38% vs 13%, P = .02). Operative mortality occurred in 1 group I patient (4%) at the time of biventricular conversion and 2 group II patients (15%) during the Ross procedure. After a 5.2-year (IQR, 3.2-7.4) follow-up there were 2 additional mortalities in each group, all unrelated to cardiac disease.When native LVOT in interrupted aortic arch/VSD is unsuitable for systemic outflow, size and location of the VSD can be used to tailor the surgical approach to establish biventricular circulation with favorable intermediate-term outcomes.

For univentricular heart patients, the Fontan operation creates a unique non-physiologic circulation where the pulmonary arteries are directly supplied from the systemic venous blood return, leading to chronic non-pulsatile low-shear-rate pulmonary blood flow. Computational fluid dynamic (CFD) simulations are widely used in cardiovascular biofluid studies and a Newtonian fluid assumption is common since blood acts as a Newtonian fluid in large arteries. Although blood viscosity increases exponentially in low-shear-rate flow environments, a Newtonian assumption is still conventionally used in both experimental and CFD studies of the low-shear-rate Fontan circulation. The error introduced by a Newtonian assumption in this setting has not been thoroughly evaluated. Recent in vitro studies have demonstrated that non-Newtonian effects are substantial in the Fontan circulation. However, no previous studies have used CFD to systemically investigate non-Newtonian effects in Fontan simulations. Thus the role of shear-rate-dependent non-Newtonian blood viscosity in this pathophysiology is still unclear. In this study we used a computational approach to compare flow behavior between a non-Newtonian fluid and a Newtonian fluid in a simplified model of the Fontan circulation over a wide range of experimental conditions. We examined important clinical metrics in Fontan hemodynamics: shear stress, power loss, pulmonary flow distribution, viscous dissipation, and non-Newtonian importance factors. Our results suggest that the Newtonian fluid assumption for blood introduces considerable error into the simulations of the Fontan circulation, where the fluid environment is predominated by low-shear-rate flow.

Background Diabetic ketoacidosis (DKA) is a common complication affecting patients with type 1 diabetes, and DKA is associated with dehydration and electrolyte abnormalities. Supraventricular tachycardia (SVT), although a common tachydysrhythmia in the pediatric population, remains a rare entity in patients presenting with DKA. Case Report We describe a case of first-time SVT in an adolescent patient with DKA and recent methamphetamine abuse, with both factors likely predisposing him to develop a tachydysrhythmia. Why Should an Emergency Physician Be Aware of This? SVT can be present in a patient who has concomitant recent stimulant intake and DKA. A trial of abortive therapy, such as adenosine, should be considered upon diagnosis.

Background For the growing patient population with congenital heart disease (CHD), improving clinical workflow, accuracy of diagnosis, and efficiency of analyses are considered unmet clinical needs. Cardiovascular magnetic resonance (CMR) imaging offers non-invasive and non-ionizing assessment of CHD patients. However, although CMR data facilitates reliable analysis of cardiac function and anatomy, clinical workflow mostly relies on manual analysis of CMR images, which is time consuming. Thus, an automated and accurate segmentation platform exclusively dedicated to pediatric CMR images can significantly improve the clinical workflow, as the present work aims to establish. Methods Training artificial intelligence (AI) algorithms for CMR analysis requires large annotated datasets, which are not readily available for pediatric subjects and particularly in CHD patients. To mitigate this issue, we devised a novel method that uses a generative adversarial network (GAN) to synthetically augment the training dataset via generating synthetic CMR images and their corresponding chamber segmentations. In addition, we trained and validated a deep fully convolutional network (FCN) on a dataset, consisting of $$64$$ 64 pediatric subjects with complex CHD, which we made publicly available. Dice metric, Jaccard index and Hausdorff distance as well as clinically-relevant volumetric indices are reported to assess and compare our platform with other algorithms including U-Net and cvi42, which is used in clinics. Results For congenital CMR dataset, our FCN model yields an average Dice metric of $$91.0\mathrm{\%}$$ 91.0 % and $$86.8\mathrm{\%}$$ 86.8 % for LV at end-diastole and end-systole, respectively, and $$84.7\mathrm{\%}$$ 84.7 % and $$80.6\mathrm{\%}$$ 80.6 % for RV at end-diastole and end-systole, respectively. Using the same dataset, the cvi42, resulted in $$73.2\mathrm{\%}$$ 73.2 % , $$71.0\mathrm{\%}$$ 71.0 % , $$54.3\mathrm{\%}$$ 54.3 % and $$53.7\mathrm{\%}$$ 53.7 % for LV and RV at end-diastole and end-systole, and the U-Net architecture resulted in $$87.4\mathrm{\%}$$ 87.4 % , $$83.9\mathrm{\%}$$ 83.9 % , $$81.8\mathrm{\%}$$ 81.8 % and $$74.8\mathrm{\%}$$ 74.8 % for LV and RV at end-diastole and end-systole, respectively. Conclusions The chambers’ segmentation results from our fully-automated method showed strong agreement with manual segmentation and no significant statistical difference was found by two independent statistical analyses. Whereas cvi42 and U-Net segmentation results failed to pass the t-test. Relying on these outcomes, it can be inferred that by taking advantage of GANs, our method is clinically relevant and can be used for pediatric and congenital CMR segmentation and analysis.

Introduction: Pulmonary atresia with intact ventricular septum (PAIVS) is surgically managed with biventricular repair (2V), 1.5 ventricle palliation (1.5V), or single ventricle palliation (1V). Cardiopulmonary exercise testing (CPET) has been increasingly utilized in these patients. However, prognostic ability of CPET is limited by achievement of maximal exercise effort [respiratory exchange ratio (RER) > 1.1]. Even during submaximal exercise, the VE/VCO2 can impact peak VO2. This study aims to identify CPET differences in 1V, 1.5V, and 2V PAIVS patients. Methods: A retrospective, cross-sectional study was performed, identifying PAIVS patients undergoing CPET. Contemporaneous echocardiography and CMR data was collected. CPET measures were compared by treatment group using ANOVA, Kruskal-Wallis, and chi-squared test, as appropriate. Comparisons of VE/VCO2 between individual groups were performed using Wilcoxon test. Univariate associations with VE/VCO2 were determined using Pearson correlation. Results: Nineteen PAIVS patients were identified (age 12.4 ± 0.68; seven 1V, five 1.5V, seven 2V). Only 7/19 (36.8%) patients achieved RER > 1.1. Sex, age, RER, peak VO2, ventilatory anaerobic threshold, O2 pulse, BSA-adjusted O2 pulse, peak HR, and HR reserve did not differ between treatment groups. The VE/VCO2 ratio was different (p=0.037), with lower VE/VCO2 in 1.5V vs. 1V (p=0.021). Across all PAIVS patients, univariate associations with lower VE/VCO2 were male sex, higher BSA, hematocrit, and O2 pulse, and lower mitral inflow A wave velocity. In the 1.5V and 2V patients, higher RVEF and RV stroke volume by CMR were associated with lower VE/VCO2. Conclusions: The 1.5V palliation of PAIVS may be associated with better gas exchange efficiency compared to 1V palliation, while 2V patients were not different from either 1V or 1.5V. BSA-adjusted O2 pulse did not vary between treatment pathways, suggesting similar stroke volume response across all patients.

The Fontan procedure for univentricular heart defects creates a unique circulation where all pulmonary blood flow is passively supplied directly from systemic veins. Computational simulations, aimed at optimizing the surgery, have assumed blood to be a Newtonian fluid without evaluating the potential error introduced by this assumption. We compared flow behavior between a non-Newtonian blood analog (0.04% xanthan gum) and a control Newtonian fluid (45% glycerol) in a simplified model of the Fontan circulation. Particle image velocimetry was used to examine flow behavior at two different cardiac outputs and two caval blood flow distributions. Pressure and flow rates were measured at each inlet and outlet. Velocity, shear strain, and shear stress maps were derived from velocity data. Power loss was calculated from pressure, flow, and velocity data. Power loss was increased in all test conditions with xanthan gum vs. glycerol (mean 10±2.9% vs. 5.6±1.3%, p=0.032). Pulmonary blood flow distribution differed in all conditions, more so at low cardiac output. Caval blood flow mixing patterns and shear stress were also qualitatively different between the solutions in all conditions. We conclude that assuming blood to be a Newtonian fluid introduces considerable error into simulations of the Fontan circulation, where low-shear flow predominates.

The Fontan procedure for univentricular heart defects creates a nonphysiologic circulation where systemic venous blood drains directly into the pulmonary arteries, leading to multiorgan dysfunction secondary to chronic low-shear nonpulsatile pulmonary blood flow and central venous hypertension. Although blood viscosity increases exponentially in this low-shear environment, the role of shear-dependent (“non-Newtonian”) blood viscosity in this pathophysiology is unclear. We studied three-dimensional (3D)-printed Fontan models in an in vitro flow loop with a Philips 3-T magnetic resonance imaging (MRI) scanner. A 4D flow phase-contrast sequence was used to acquire a time-varying 3D velocity field for each experimental condition. On the basis of blood viscosity of a cohort of patients who had undergone the Fontan procedure, it was decided to use 0.04% xanthan gum as a non-Newtonian blood analog; 45% glycerol was used as a Newtonian control fluid. MRI data were analyzed using GTFlow and MATLAB software. The primary outcome, power loss, was significantly higher with the Newtonian fluid [14.8 (13.3, 16.4) vs. 8.1 (6.4, 9.8)%, medians with 95% confidence interval, P < 0.0001]. The Newtonian fluid also demonstrated marginally higher right pulmonary artery flow, marginally lower shear stress, and a trend toward higher caval flow mixing. Outcomes were modulated by Fontan model complexity, cardiac output, and caval flow ratio. Vortexes, helical flow, and stagnant flow were more prevalent with the non-Newtonian fluid. Our data demonstrate that shear-dependent viscosity significantly alters qualitative flow patterns, power loss, pulmonary flow distribution, shear stress, and caval flow mixing in synthetic models of the Fontan circulation. Potential clinical implications include effects on exercise capacity, ventilation-perfusion matching, risk of pulmonary arteriovenous malformations, and risk of thromboembolism. NEW & NOTEWORTHY Although blood viscosity increases exponentially in low-shear environments, the role of shear-dependent (“non-Newtonian”) blood viscosity in the pathophysiology of the low-shear Fontan circulation is unclear. We demonstrate that shear-dependent viscosity significantly alters qualitative flow patterns, power loss, pulmonary flow distribution, shear stress, and caval flow mixing in synthetic models of the Fontan circulation. Potential clinical implications include effects on exercise capacity, ventilation-perfusion matching, risk of pulmonary arteriovenous malformations, and risk of thromboembolism.

Cardiac MRI (CMR) allows non-invasive, non-ionizing assessment of cardiac function and anatomy in patients with congenital heart disease (CHD). The utility of CMR as a non-invasive imaging tool for evaluation of CHD have been growing exponentially over the past decade. The algorithms based on artificial intelligence (AI), and in particular, deep learning, have rapidly become a methodology of choice for analyzing CMR. A wide range of applications for AI have been developed to tackle challenges in various aspects of CMR, and significant advances have also been made from image acquisition to image analysis and diagnosis. We include an overview of AI definitions, different architectures, and details on well-known methods. This paper reviews the major deep learning concepts used for analyses of patients with CHD. In the end, we have summarized a list of open challenges and concerns to be considered for future studies.

Objective To characterize changes in Fontan conduit size over time and determine if cross-sectional area (CSA) affects cardiac output, pulmonary artery growth, and exercise capacity. Methods We conducted a retrospective cross-sectional study of patients with Fontan physiology who underwent cardiac magnetic resonance imaging or cardiac catheterization between January 2013 and October 2019. We collected Fontan and pulmonary artery measurements, hemodynamic data, and cardiopulmonary exercise test data. We identified 158 patients with an extracardiac Fontan. We measured minimum and mean Fontan conduit CSA and assessed whether these correlated with Nakata index, cardiac index, or exercise capacity. Results Minimum Fontan CSA decreased by a median of 33% (24%, 40%) during a mean follow-up of 9.6 years. Median percentage decrease in Fontan CSA did not differ among 16-, 18-, and 20-mm conduits (P = .29). There was a significant decrease in the minimum Fontan CSA (33% [25%, 41%]) starting less than 1-year post-Fontan. Median Nakata index was 177.6 mm2/m2 (149.1, 210.8) and was not associated with Fontan CSA/BSA (ρ = 0.09, P = .29). Fontan CSA/BSA was not associated with cardiac index (ρ = –0.003, P = .97). A larger Fontan CSA/BSA had a modest correlation with % predicted oxygen consumption (ρ = 0.31, P = .013). Conclusions Fontan conduit CSA decreases as early as 6 months post-Fontan. The minimum Fontan CSA/BSA was not associated with cardiac index or pulmonary artery size but did correlate with % predicted peak oxygen consumption.

BACKGROUND: Patients with pulmonary atresia with intact ventricular septum and critical pulmonary stenosis (PAIVS/CPS) have wide variation in right ventricle (RV) size, systolic function, and diastolic function at birth. Establishment of antegrade pulmonary blood flow creates the potential for RV dilation from chronic pulmonary insufficiency. Future surgical decisions are based on RV size and function, largely supported by longitudinal studies of patients with Tetralogy of Fallot (TOF). Given potential differences in RV physiology and lack of similar data in PAIVS/CPS, the objective of this study was to determine differences in RV size, systolic function, and diastolic function between patients with PAIVS/CPS versus TOF. METHODS: We retrospectively collected cardiovascular magnetic resonance (CMR) data in 27 patients with PAIVS/CPS (ages 13.3 ± 8.8 years) and 78 with TOF (11.4 ± 5.4 years). RV volumes, ejection fraction (EF), regurgitant fraction, end-diastolic forward flow across the pulmonary valve, and right atrial cross-sectional area were calculated. RESULTS: There was no difference between the groups in RV end-diastolic volume (RVEDVi), RVEF, or pulmonary regurgitation. RVEF tended to decrease in TOF when RVEDVi exceeded 164 ml/m(2). In PAIVS/CPS, RVEDVi less frequently reached 164 ml/m(2) and was not associated with RVEF. There was worse RV diastolic dysfunction in PAIVS/CPS, with 1.5 times larger right atrial area and two times higher pulmonary end-diastolic forward flow (p < 0.0001). CONCLUSIONS: Patients with PAIVS/CPS have similar RV size, systolic function, and pulmonary regurgitation as TOF. However, impaired RV diastolic function may limit extremes of RV dilatation and impact long-term management of PAIVS/CPS.

Biological membranes organize and compartmentalize cell signaling into discrete microdomains, a process that often involves stable, cholesterol-rich platforms that facilitate protein–protein interactions. Polarized cells with distinct apical and basolateral cell processes rely on such compartmentalization to maintain proper function. In the cochlea, a variety of highly polarized sensory and non-sensory cells are responsible for the early stages of sound processing in the ear, yet little is known about the mechanisms that traffic and organize signaling complexes within these cells. We sought to determine the prevalence, localization, and protein composition of cholesterol-rich lipid microdomains in the cochlea. Lipid raft components, including the scaffolding protein caveolin and the ganglioside GM1, were found in sensory, neural, and glial cells. Mass spectrometry of detergent-resistant membrane (DRM) fractions revealed over 600 putative raft proteins associated with subcellular localization, trafficking, and metabolism. Among the DRM constituents were several proteins involved in human forms of deafness including those involved in ion homeostasis, such as the potassium channel KCNQ1, the co-transporter SLC12A2, and gap junction proteins GJA1 and GJB6. The presence of caveolin in the cochlea and the abundance of proteins in cholesterol-rich DRM suggest that lipid microdomains play a significant role in cochlear physiology. Biological significance Although mechanisms underlying cholesterol synthesis, homeostasis, and compartmentalization in the ear are poorly understood, there are several lines of evidence indicating that cholesterol is a key modulator of cochlear function. Depletion of cholesterol in mature sensory cells alters calcium signaling, changes excitability during development, and affects the biomechanical processes in outer hair cells that are responsible for hearing acuity. More recently, we have established that the cholesterol-modulator beta-cyclodextrin is capable of inducing significant and permanent hearing loss when delivered subcutaneously at high doses. We hypothesize that proteins involved in cochlear homeostasis and otopathology are partitioned into cholesterol-rich domains. The results of a large-scale proteomic analysis point to metabolic processes, scaffolding/trafficking, and ion homeostasis as particularly associated with cholesterol microdomains. These data offer insight into the proteins and protein families that may underlie cholesterol-mediated effects in sensory cell excitability and cyclodextrin ototoxicity.

In this study, we present a case of prenatally diagnosed tetralogy of Fallot with a double aortic arch, correlating images from fetal echocardiography, transthoracic echocardiography, and cardiac MRI.

The non-Newtonian behavior of blood (i.e. the dependence of viscosity on shear rate and shear stress) is most apparent in low-shear regions such as veins. For simplification, computational simulations aimed at optimizing the Fontan procedure have assumed blood to be a Newtonian fluid with shear

Anomalous origin of a pulmonary artery from the ascending aorta is a congenital defect that can be complicated by pulmonary arterial hypertension, typically due to vascular disease if the anomaly is left uncorrected past 6 months of age. We describe a unique case of severe pulmonary arterial hypertension with this defect in a 1-month-old infant unexpectedly caused instead by bronchial compression from her dilated left pulmonary artery.

After the Fontan procedure, patients with univentricular hearts can experience long-term complications due to chronic low-shear non-pulsatile pulmonary blood flow. We sought to evaluate hemorheology and its relationship to hemodynamics in children with univentricular hearts. We hypothesized that low-shear blood viscosity and red blood cell (RBC) aggregation would be associated with increased pulmonary vascular resistance (PVR) and decreased pulmonary blood flow (PBF). We performed a cross-sectional analysis of 62 children undergoing cardiac catheterization-20 with isolated atrial septal defect (ASD), 22 status post Glenn procedure (Glenn), and 20 status post Fontan procedure (Fontan). Shear-dependent blood viscosity, RBC aggregation and deformability, complete blood count, coagulation panel, metabolic panel, fibrinogen, and erythrocyte sedimentation rate were measured. PVR and PBF were calculated using the Fick equation. Group differences were analyzed by ANOVA and correlations by linear regression. Blood viscosity at all shear rates was higher in Glenn and Fontan, partially due to normocytic anemia in ASD. RBC aggregation and deformability were similar between all groups. Low-shear viscosity negatively correlated with PBF in Glenn and Fontan only (R (2) = 0.27, p < 0.001); it also negatively correlated with pulmonary artery pressure in Glenn (R (2) = 0.15, p = 0.01), and positively correlated with PVR in Fontan (R (2) = 0.28, p = 0.02). Our data demonstrate that elevated low-shear blood viscosity is associated with negative hemodynamic perturbations in a passive univentricular pulmonary circulation, but not in a pulsatile biventricular pulmonary circulation.

Background The rheumatoid arthritis (RA) shared epitope (SE), a major risk factor for severe disease, is a five amino acid motif in the third allelic hypervariable region of the HLA-DRβ chain. The molecular mechanisms by which the SE affects susceptibility to – and severity of - RA are unknown. We have recently demonstrated that the SE acts as a ligand that interacts with cell surface calreticulin (CRT) and activates innate immune signaling. In order to better understand the molecular basis of SE-RA association, here we have undertaken to map the SE binding site on CRT. Principal Findings Surface plasmon resonance (SPR) experiments with domain deletion mutants suggested that the SE binding site is located in the P-domain of CRT. The role of this domain as a SE-binding region was further confirmed by a sulfosuccinimidyl-2-[6-(biotinamido)-2-(p-azido-benzamido) hexanoamido] ethyl-1,3-dithiopropionate (sulfo-SBED) photoactive cross-linking method. In silico analysis of docking interactions between a conformationally intact SE ligand and the CRT P-domain predicted the region within amino acid residues 217–224 as a potential SE binding site. Site-directed mutagenesis demonstrated involvement of residues Glu217 and Glu223 - and to a lesser extent residue Asp220 - in cell-free SPR-based binding and signal transduction assays. Significance We have characterized here the molecular basis of a novel ligand-receptor interaction between the SE and CRT. The interaction represents a structurally and functionally well-defined example of cross talk between the adaptive and innate immune systems that could advance our understanding of the pathogenesis of autoimmunity.