Decreased erythrocyte aggregation in Glenn and Fontan: univentricular circulation as a rheologic disease model.

BACKGROUND: In the Fontan palliation for single ventricle heart disease (SVHD), pulmonary blood flow is non-pulsatile/passive, low velocity, and low shear, making viscous power loss a critical determinant of cardiac output. The rheologic properties of blood in SVHD patients are essential for understanding and modulating their limited cardiac output and they have not been systematically studied. We hypothesize that viscosity is decreased in single ventricle circulation. METHODS: We evaluated whole blood viscosity, red blood cell (RBC) aggregation, and RBC deformability to evaluate changes in healthy children and SVHD patients. We altered suspending media to understand cellular and plasma differences contributing to rheologic differences. RESULTS: Whole blood viscosity was similar between SVHD and healthy at their native hematocrits, while viscosity was lower at equivalent hematocrits for SVHD patients. RBC deformability is increased, and RBC aggregation is decreased in SVHD patients. Suspending SVHD RBCs in healthy plasma resulted in increased RBC aggregation and suspending healthy RBCs in SVHD plasma resulted in lower RBC aggregation. CONCLUSIONS: Hematocrit corrected blood viscosity is lower in SVHD vs. healthy due to decreased RBC aggregation and higher RBC deformability, a viscous adaptation of blood in patients whose cardiac output is dependent on minimizing viscous power loss. IMPACT: Patients with single ventricle circulation have decreased red blood cell aggregation and increased red blood cell deformability, both of which result in a decrease in blood viscosity across a large shear rate range. Since the unique Fontan circulation has very low-shear and low velocity flow in the pulmonary arteries, blood viscosity plays an increased role in vascular resistance, therefore this work is the first to describe a novel mechanism to target pulmonary vascular resistance as a modifiable risk factor. This is a novel, modifiable risk factor in this patient population.

Screening left ventricular systolic dysfunction in children using intrinsic frequencies of carotid pressure waveforms measured by a novel smartphone-based device.

Objective.Children with heart failure have higher rates of emergency department utilization, health care expenditure, and hospitalization. Therefore, a need exists for a simple, non-invasive, and inexpensive method of screening for left ventricular (LV) dysfunction. We recently demonstrated the practicality and reliability of a wireless smartphone-based handheld device in capturing carotid pressure waveforms and deriving cardiovascular intrinsic frequencies (IFs) in children with normal LV function. Our goal in this study was to demonstrate that an IF-based machine learning method (IF-ML) applied to noninvasive carotid pressure waveforms can distinguish between normal and abnormal LV ejection fraction (LVEF) in pediatric patients.Approach. Fifty patients ages 0 to 21 years underwent LVEF measurement by echocardiogram or cardiac magnetic resonance imaging. On the same day, patients had carotid waveforms recorded using Vivio. The exclusion criterion was known vascular disease that would interfere with obtaining a carotid artery pulse. We adopted a hybrid IF- Machine Learning (IF-ML) method by applying physiologically relevant IF parameters as inputs to Decision Tree classifiers. The threshold for low LVEF was chosen as <50%.Main results.The proposed IF-ML method was able to detect an abnormal LVEF with an accuracy of 92% (sensitivity = 100%, specificity = 89%, area under the curve (AUC) = 0.95). Consistent with previous clinical studies, the IF parameterω1was elevated among patients with reduced LVEF.Significance.A hybrid IF-ML method applied on a carotid waveform recorded by a hand-held smartphone-based device can differentiate between normal and abnormal LV systolic function in children with normal cardiac anatomy.

Progression in Fontan conduit stenosis and hemodynamic impact during childhood and adolescence.

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.

Biventricular Repair in Interrupted Aortic Arch and Ventricular Septal Defect With a Small Left Ventricular Outflow Tract.

BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

Fully­automated deep­learning segmentation of pediatric cardiovascular magnetic resonance of patients with complex congenital heart diseases.

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 [Formula: see text] 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 [Formula: see text] and [Formula: see text] for LV at end-diastole and end-systole, respectively, and [Formula: see text] and [Formula: see text] for RV at end-diastole and end-systole, respectively. Using the same dataset, the cvi42, resulted in [Formula: see text], [Formula: see text], [Formula: see text] and [Formula: see text] for LV and RV at end-diastole and end-systole, and the U-Net architecture resulted in [Formula: see text], [Formula: see text], [Formula: see text] and [Formula: see text] 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.

Proof-of-concept for a non-invasive, portable, and wireless device for cardiovascular monitoring in pediatric patients.

Measurement of cardiac function is vital for the health of pediatric patients with heart disease. Standard tools to measure function including echocardiogram and magnetic residence imaging are time intensive, costly, and have limited accessibility. The Vivio is a novel, non-invasive, handheld device that screens for cardiac dysfunction by analyzing intrinsic frequencies (IF) ω1 and ω2 of carotid artery waveforms. Prior studies demonstrated that left ventricular ejection fraction can be derived from IFs in adults. This study 1) studies whether the Vivio can capture carotid arterial pulse waveform data in children ages 0-19 years old; 2) tests the performance of two sensor head geometries, one larger and smaller than the standard size used in adults, designed for the pediatric population; 3) compares the IFs between pediatric age groups and adults with normal function. The Vivio successfully measured a carotid artery waveform in all children over 5 years old and 28% of children under the age of five. The small head did not accurately measure a waveform in any age group. One-way analysis of variance (ANOVA) demonstrated a difference in the IF ω1 between the adult and pediatric cohorts (F = 7.3, Prob>F = 0.0001). Post host analysis demonstrated a difference between the adult cohort (ω1 = 99 +/- 5 bpm) and the cohorts ages 0-4 (ω1 = 111 +/- 2 bpm; p = 0.0006) and 15-19 years old (ω1 = 105 +/-5 bpm; p = 0.02). One-way ANOVA demonstrated a difference in the IF ω2 between the adult and pediatric cohorts (F = 4.8, Prob>F = 0.003), specifically between the adult (ω2 = 81 +/- 13 bpm) and age 0-4 cohorts (ω2 = 48 +/- 8 bpm; p = 0.002). These results suggest that the Vivio can be used to capture carotid pulse waveform data in pediatric populations and that the data produced can be used to measure intrinsic frequencies.

Artificial intelligence in pediatric and adult congenital cardiac MRI: an unmet clinical need.

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.

A 4D flow MRI evaluation of the impact of shear-dependent fluid viscosity on in vitro Fontan circulation flow.

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.

Methamphetamine-Induced Tachydysrhythmia in an Adolescent in Diabetic Ketoacidosis.

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.

Differences in Right Ventricular Physiologic Response to Chronic Volume Load in Patients with Repaired Pulmonary Atresia Intact Ventricular Septum/Critical Pulmonary Stenosis Versus Tetralogy of Fallot.

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/m2. In PAIVS/CPS, RVEDVi less frequently reached 164 ml/m2 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.

Experimental Investigation of the Effect of Non-Newtonian Behavior of Blood Flow in the Fontan Circulation.

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.

Prenatal diagnosis of tetralogy of Fallot with a double aortic arch.

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.

Left bronchial compression and pulmonary hypertension related to anomalous right pulmonary artery.

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.

Elevated Low-Shear Blood Viscosity is Associated with Decreased Pulmonary Blood Flow in Children with Univentricular Heart Defects.

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.

Localization and proteomic characterization of cholesterol-rich membrane microdomains in the inner ear.

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.