A deep learning approach for fully automated cardiac shape modeling in tetralogy of Fallot.

BACKGROUND: Cardiac shape modeling is a useful computational tool that has provided quantitative insights into the mechanisms underlying dysfunction in heart disease. The manual input and time required to make cardiac shape models, however, limits their clinical utility. Here we present an end-to-end pipeline that uses deep learning for automated view classification, slice selection, phase selection, anatomical landmark localization, and myocardial image segmentation for the automated generation of three-dimensional, biventricular shape models. With this approach, we aim to make cardiac shape modeling a more robust and broadly applicable tool that has processing times consistent with clinical workflows. METHODS: Cardiovascular magnetic resonance (CMR) images from a cohort of 123 patients with repaired tetralogy of Fallot (rTOF) from two internal sites were used to train and validate each step in the automated pipeline. The complete automated pipeline was tested using CMR images from a cohort of 12 rTOF patients from an internal site and 18 rTOF patients from an external site. Manually and automatically generated shape models from the test set were compared using Euclidean projection distances, global ventricular measurements, and atlas-based shape mode scores. RESULTS: The mean absolute error (MAE) between manually and automatically generated shape models in the test set was similar to the voxel resolution of the original CMR images for end-diastolic models (MAE = 1.9 ± 0.5 mm) and end-systolic models (MAE = 2.1 ± 0.7 mm). Global ventricular measurements computed from automated models were in good agreement with those computed from manual models. The average mean absolute difference in shape mode Z-score between manually and automatically generated models was 0.5 standard deviations for the first 20 modes of a reference statistical shape atlas. CONCLUSIONS: Using deep learning, accurate three-dimensional, biventricular shape models can be reliably created. This fully automated end-to-end approach dramatically reduces the manual input required to create shape models, thereby enabling the rapid analysis of large-scale datasets and the potential to deploy statistical atlas-based analyses in point-of-care clinical settings. Training data and networks are available from cardiacatlas.org.

Spectrum of Viral Pathogens Identified in Children with Clinical Myocarditis (Pre-Coronavirus Disease-2019, 2000-2018): Etiologic Agent Versus Innocent Bystander.

OBJECTIVE: To identify the etiologies of viral myocarditis in children in the pre-coronavirus disease 2019 era. STUDY DESIGN: This was a retrospective review of all patients (age <18 years) diagnosed with myocarditis and hospitalized at Rady Children's Hospital San Diego between 2000 and 2018. RESULTS: Twenty-nine patients met inclusion criteria. Of 28 (97%) patients who underwent testing for viruses, polymerase chain reaction was used in 24 of 28 (86% of cases), and 16 of 24 (67%) detected a virus. Pathogens were rhinovirus (6), influenza A/B (4), respiratory syncytial virus (RSV) (3), coronavirus (3), parvovirus B19 (2), adenovirus (2), and coxsackie B5 virus, enterovirus, and parainfluenza virus type 2 in one case each. Six (21%) patients had no pathogen detected but imaging and other laboratory test results were compatible with myocarditis. Age 0-2 years was associated with RSV, influenza A/B, coronavirus, and enteroviruses (P < .001). Twenty-one patients (72%) experienced full clinical recovery. Three patients (10%) required venoarterial extracorporeal membrane oxygenation (VA-ECMO), and all 3 recovered. Three others (10%) required and underwent successful cardiac transplantation without complications. Two patients (7%) died 9-10 days after hospitalization (1 had RSV and 1 had influenza A/B). Two other patients presented with complete atrioventricular block; 1 case (rhinovirus) resolved spontaneously, and 1 (coronavirus) resolved after support with VA-ECMO. Age <2 years, female sex, lower ejection fraction at admission, and greater initial and peak levels of brain natriuretic peptide were significant predictors of critical outcomes (use of VA-ECMO, listing for cardiac transplantation, and death). CONCLUSIONS: Viral nucleic acid-based testing revealed a wider spectrum of viruses that could be associated with myocarditis in children than previously reported and traditionally anticipated. A predilection of certain pathogens in the very young patients was observed. Whether the observed range of viral agents reflects an undercurrent of change in viral etiology or viral detection methods is unclear, but the wider spectrum of viral pathogens found underscores the usefulness of polymerase chain reaction testing to explore possible viral etiologies of myocarditis in children.

Right-left ventricular shape variations in tetralogy of Fallot: associations with pulmonary regurgitation.

BACKGROUND: Relationships between right ventricular (RV) and left ventricular (LV) shape and function may be useful in determining optimal timing for pulmonary valve replacement in patients with repaired tetralogy of Fallot (rTOF). However, these are multivariate and difficult to quantify. We aimed to quantify variations in biventricular shape associated with pulmonary regurgitant volume (PRV) in rTOF using a biventricular atlas. METHODS: In this cross-sectional retrospective study, a biventricular shape model was customized to cardiovascular magnetic resonance (CMR) images from 88 rTOF patients (median age 16, inter-quartile range 11.8-24.3 years). Morphometric scores quantifying biventricular shape at end-diastole and end-systole were computed using principal component analysis. Multivariate linear regression was used to quantify biventricular shape associations with PRV, corrected for age, sex, height, and weight. Regional associations were confirmed by univariate correlations with distances and angles computed from the models, as well as global systolic strains computed from changes in arc length from end-diastole to end-systole. RESULTS: PRV was significantly associated with 5 biventricular morphometric scores, independent of covariates, and accounted for 12.3% of total shape variation (p < 0.05). Increasing PRV was associated with RV dilation and basal bulging, in conjunction with decreased LV septal-lateral dimension (LV flattening) and systolic septal motion towards the RV (all p < 0.05). Increased global RV radial, longitudinal, circumferential and LV radial systolic strains were significantly associated with increased PRV (all p < 0.05). CONCLUSION: A biventricular atlas of rTOF patients quantified multivariate relationships between left-right ventricular morphometry and wall motion with pulmonary regurgitation. Regional RV dilation, LV reduction, LV septal-lateral flattening and increased RV strain were all associated with increased pulmonary regurgitant volume. Morphometric scores provide simple metrics linking mechanisms for structural and functional alteration with important clinical indices.

Atlas-based methods for efficient characterization of patient-specific ventricular activation patterns.

AIMS: Ventricular activation patterns can aid clinical decision-making directly by providing spatial information on cardiac electrical activation or indirectly through derived clinical indices. The aim of this work was to derive an atlas of the major modes of variation of ventricular activation from model-predicted 3D bi-ventricular activation time distributions and to relate these modes to corresponding vectorcardiograms (VCGs). We investigated how the resulting dimensionality reduction can improve and accelerate the estimation of activation patterns from surface electrogram measurements. METHODS AND RESULTS: Atlases of activation time (AT) and VCGs were derived using principal component analysis on a dataset of simulated electrophysiology simulations computed on eight patient-specific bi-ventricular geometries. The atlases provided significant dimensionality reduction, and the modes of variation in the two atlases described similar features. Utility of the atlases was assessed by resolving clinical waveforms against them and the VCG atlas was able to accurately reconstruct the patient VCGs with fewer than 10 modes. A sensitivity analysis between the two atlases was performed by calculating a compact Jacobian. Finally, VCGs generated by varying AT atlas modes were compared with clinical VCGs to estimate patient-specific activation maps, and the resulting errors between the clinical and atlas-based VCGs were less than those from more computationally expensive method. CONCLUSION: Atlases of activation and VCGs represent a new method of identifying and relating the features of these high-dimensional signals that capture the major sources of variation between patients and may aid in identifying novel clinical indices of arrhythmia risk or therapeutic outcome.

Antiarrhythmic Treatment Duration and Tachycardia Recurrence in Infants with Supraventricular Tachycardia.

We sought to assess the effect of a shorter medication treatment course (up to 4-6 months of age) on the recurrence of infantile supraventricular tachycardia (SVT). This was a retrospective review of infants with SVT diagnosed at age 0-12 months at Rady Children's Hospital (2010-2017). Infants with structural congenital heart disease, automatic tachycardias, atrial flutter, or lack of follow-up data were excluded. Seventy-four infants met criteria. Median age at diagnosis was 6 days (IQR 0-21 days); 28.4% presented with fetal tachycardia. Median gestational age was 38.4 weeks (IQR 36-40), 30% were preterm. Median age at medication discontinuation was 6.7 months (IQR 4.6-9.8). Therapy was stopped at younger age in patients managed by pediatric electrophysiologist (vs. general pediatric cardiologist): 4.9 vs. 8.6 months (p = 0.03). Thirty-eight patients (51.4%) were treated for < 6 months; 32.4% for 6-12 months, and 16.2% for > 12 months. SVT recurrence was similar for these groups: 13.2% vs. 16.7%, and 33.3%, respectively, (p = 0.27). Most patients with recurrence required emergency care, though none had significant adverse outcomes. Infants with SVT and structurally normal cardiac anatomy, who remain recurrence free on a single agent, have no increased risk of recurrence with shorter treatment courses of 4-6 months, compared to traditional treatment duration of 6-12 months.

Mammillothalamic Disconnection Alters Hippocampocortical Oscillatory Activity and Microstructure: Implications for Diencephalic Amnesia.

Diencephalic amnesia can be as debilitating as the more commonly known temporal lobe amnesia, yet the precise contribution of diencephalic structures to memory processes remains elusive. Across four cohorts of male rats, we used discrete lesions of the mammillothalamic tract to model aspects of diencephalic amnesia and assessed the impact of these lesions on multiple measures of activity and plasticity within the hippocampus and retrosplenial cortex. Lesions of the mammillothalamic tract had widespread indirect effects on hippocampocortical oscillatory activity within both theta and gamma bands. Both within-region oscillatory activity and cross-regional synchrony were altered. The network changes were state-dependent, displaying different profiles during locomotion and paradoxical sleep. Consistent with the associations between oscillatory activity and plasticity, complementary analyses using several convergent approaches revealed microstructural changes, which appeared to reflect a suppression of learning-induced plasticity in lesioned animals. Together, these combined findings suggest a mechanism by which damage to the medial diencephalon can impact upon learning and memory processes, highlighting an important role for the mammillary bodies in the coordination of hippocampocortical activity.SIGNIFICANCE STATEMENT Information flow within the Papez circuit is critical to memory. Damage to ascending mammillothalamic projections has consistently been linked to amnesia in humans and spatial memory deficits in animal models. Here we report on the changes in hippocampocortical oscillatory dynamics that result from chronic lesions of the mammillothalamic tract and demonstrate, for the first time, that the mammillary bodies, independently of the supramammillary region, contribute to frequency modulation of hippocampocortical theta oscillations. Consistent with the associations between oscillatory activity and plasticity, the lesions also result in a suppression of learning-induced plasticity. Together, these data support new functional models whereby mammillary bodies are important for coordinating hippocampocortical activity rather than simply being a relay of hippocampal information as previously assumed.

Rapid Whole Genome Sequencing Has Clinical Utility in Children in the PICU.

OBJECTIVES: Genetic disorders are a leading contributor to mortality in the neonatal ICU and PICU in the United States. Although individually rare, there are over 6,200 single-gene diseases, which may preclude a genetic diagnosis prior to ICU admission. Rapid whole genome sequencing is an emerging method of diagnosing genetic conditions in time to affect ICU management of neonates; however, its clinical utility has yet to be adequately demonstrated in critically ill children. This study evaluates next-generation sequencing in pediatric critical care. DESIGN: Retrospective cohort study. SETTING: Single-center PICU in a tertiary children's hospital. PATIENTS: Children 4 months to 18 years admitted to the PICU who were nominated between July 2016 and May 2018. INTERVENTIONS: Rapid whole genome sequencing with targeted phenotype-driven analysis was performed on patients and their parents, when parental samples were available. MEASUREMENTS AND MAIN RESULTS: A molecular diagnosis was made by rapid whole genome sequencing in 17 of 38 children (45%). In four of the 17 patients (24%), the genetic diagnoses led to a change in management while in the PICU, including genome-informed changes in pharmacotherapy and transition to palliative care. Nine of the 17 diagnosed children (53%) had no dysmorphic features or developmental delay. Eighty-two percent of diagnoses affected the clinical management of the patient and/or family after PICU discharge, including avoidance of biopsy, administration of factor replacement, and surveillance for disorder-related sequelae. CONCLUSIONS: This study demonstrates a retrospective evaluation for undiagnosed genetic disease in the PICU and clinical utility of rapid whole genome sequencing in a portion of critically ill children. Further studies are needed to identify PICU patients who will benefit from rapid whole genome sequencing early in PICU admission when the underlying etiology is unclear.

Evaluation and management of bradycardia in neonates and children.

Heart rate is commonly used in pediatric early warning scores. Age-related changes in the anatomy and physiology of infants and children produce normal ranges for electrocardiogram features that differ from adults and vary with age. Bradycardia is defined as a heart rate below the lowest normal value for age. Pediatric bradycardia most commonly manifests as sinus bradycardia, junctional bradycardia, or atrioventricular block. As a result of several different etiologies, it may occur in an entirely structurally normal heart or in association with concomitant congenital heart disease. Genetic variants in multiple genes have been described to date in the pathogenesis of inherited sinus node dysfunction or progressive cardiac conduction disorders. Management and eventual prognosis of bradycardia in the young are entirely dependent upon the underlying cause. Reasons to intervene for bradycardia are the association of related symptoms and/or the downstream risk of heart failure or pause-dependent tachyarrhythmia. The simplest aspect of severe bradycardia management is reflected in the Pediatric and Advanced Life Support (PALS) guidelines. CONCLUSION: Early diagnosis and appropriate management are critical in many cases in order to prevent sudden death, and this review critically assesses our current practice for evaluation and management of bradycardia in neonates and children. WHAT IS KNOWN: Bradycardia is defined as a heart rate below the lowest normal value for age. Age related changes in the anatomy and physiology of infants and children produce normal ranges for electrocardiogram features that differ from adults and vary with age. Pediatric bradycardia most commonly manifests as sinus bradycardia, junctional bradycardia, or atrioventricular block. WHAT IS NEW: Management and eventual prognosis of bradycardia in the young are entirely dependent upon the underlying cause. Bradycardia may occur in a structurally normal heart or in association with congenital heart disease. Genetic variants in multiple genes have been described. Reasons to intervene for bradycardia are the association of related symptoms and/or the downstream risk of heart failure or pause-dependent tachyarrhythmia. Early diagnosis and appropriate management are critical in order to prevent sudden death.

Left Ventricular Mechanical Property Changes During Acute AV Synchronous Right Ventricular Pacing in Children.

Prolonged RV pacing is recognized as a cause of LV dysfunction due to dyssynchronous activation. There are no specific longitudinal parameters known to help predict RV pacing-induced LV dysfunction. The aim of the study was to assess the acute effects of AV synchronous RV pacing on LV mechanics using echocardiographic speckle tracking. Nineteen children, aged 6-23 years, underwent echocardiographic evaluation prior to and following elective electrophysiology and ablation studies. The subjects were evaluated in sinus rhythm and later with AV synchronous RV pacing at a cycle length of 550 ms with a short AV delay of 80 ms. The echocardiographic clips were analyzed using speckle tracking methods to calculate LV circumferential and longitudinal strain, rotation and twist in all conditions. Acute RV apical pacing decreased LV longitudinal strain from 16.1 ± 3.7% in sinus rhythm to 14.4 ± 3.3% (p = 0.03) and LV base rotation from -8.4° ± 3.6° to -6.4° ± 4.0° (p = 0.04). The circumferential strain, apical rotation and LV twist were not affected. Separate analysis of subjects with no prior preexcitation showed that acute RV pacing caused significant twist reduction, from 15.9° ± 7.6° to 12.1° ± 7.0° (p = 0.02), and decreased longitudinal strain and base rotation. Patients with preexcitation had abnormalities that persisted acutely after ablation. Acute RV apical pacing causes reductions in LV base rotation, longitudinal strain and twist. The recognition of abnormal LV activation patterns may provide longitudinal clues to LV dysfunction in chronically paced patients and potential novel indices of effective CRT interventions to reverse these abnormalities.

Atlas-Based Ventricular Shape Analysis for Understanding Congenital Heart Disease.

Congenital heart disease is associated with abnormal ventricular shape that can affect wall mechanics and may be predictive of long-term adverse outcomes. Atlas-based parametric shape analysis was used to analyze ventricular geometries of eight adolescent or adult single-ventricle CHD patients with tricuspid atresia and Fontans. These patients were compared with an "atlas" of non-congenital asymptomatic volunteers, resulting in a set of z-scores which quantify deviations from the control population distribution on a patient-by-patient basis. We examined the potential of these scores to: (1) quantify abnormalities of ventricular geometry in single ventricle physiologies relative to the normal population; (2) comprehensively quantify wall motion in CHD patients; and (3) identify possible relationships between ventricular shape and wall motion that may reflect underlying functional defects or remodeling in CHD patients. CHD ventricular geometries at end-diastole and end-systole were individually compared with statistical shape properties of an asymptomatic population from the Cardiac Atlas Project. Shape analysis-derived model properties, and myocardial wall motions between end-diastole and end-systole, were compared with physician observations of clinical functional parameters. Relationships between altered shape and altered function were evaluated via correlations between atlas-based shape and wall motion scores. Atlas-based shape analysis identified a diverse set of specific quantifiable abnormalities in ventricular geometry or myocardial wall motion in all subjects. Moreover, this initial cohort displayed significant relationships between specific shape abnormalities such as increased ventricular sphericity and functional defects in myocardial deformation, such as decreased long-axis wall motion. These findings suggest that atlas-based ventricular shape analysis may be a useful new tool in the management of patients with CHD who are at risk of impaired ventricular wall mechanics and chamber remodeling.

Impairments in the early consolidation of spatial memories via group II mGluR agonism in the mammillary bodies.

mGluR2 receptors are widely expressed in limbic brain regions associated with memory, including the hippocampal formation, retrosplenial and frontal cortices, as well as subcortical regions including the mammillary bodies. mGluR2/3 agonists have been proposed as potential therapeutics for neurological and psychiatric disorders, however, there is still little known about the role of these receptors in cognitive processes, including memory consolidation. To address this, we assessed the effect of the mGluR2/3 agonist, eglumetad, on spatial memory consolidation in both mice and rats. Using the novel place preference paradigm, we found that post-sample injections of eglumetad impaired subsequent spatial discrimination when tested 6 h later. Using the immediate early gene c-fos as a marker of neural activity, we showed that eglumetad injections reduced activity in a network of limbic brain regions including the hippocampus and mammillary bodies. To determine whether the systemic effects could be replicated with more targeted manipulations, we performed post-sample infusions of the mGluR2/3 agonist 2R,4R-APDC into the mammillary bodies. This impaired novelty discrimination on a place preference task and an object-in-place task, again highlighting the role of mGluR2/3 transmission in memory consolidation and demonstrating the crucial involvement of the mammillary bodies in post-encoding processing of spatial information.

A universal biventricular coordinate system incorporating valve annuli: Validation in congenital heart disease.

Universal coordinate systems have been proposed to facilitate anatomic registration between three-dimensional images, data and models of the ventricles of the heart. However, current universal ventricular coordinate systems do not account for the outflow tracts and valve annuli where the anatomy is complex. Here we propose an extension to the 'Cobiveco' biventricular coordinate system that also accounts for the intervalvular bridges of the base and provides a tool for anatomically consistent registration between widely varying biventricular shapes. CobivecoX uses a novel algorithm to separate intervalvular bridges and assign new coordinates, including an inflow-outflow coordinate, to describe local positions in these regions uniquely and consistently. Anatomic consistency of registration was validated using curated three-dimensional biventricular shape models derived from cardiac MRI measurements in normal hearts and hearts from patients with congenital heart diseases. This new method allows the advantages of universal cardiac coordinates to be used for three-dimensional ventricular imaging data and models that include the left and right ventricular outflow tracts and valve annuli.

Biventricular shape modes discriminate pulmonary valve replacement in tetralogy of Fallot better than imaging indices.

Current indications for pulmonary valve replacement (PVR) in repaired tetralogy of Fallot (rTOF) rely on cardiovascular magnetic resonance (CMR) image-based indices but are inconsistently applied, lead to mixed outcomes, and remain debated. This study aimed to test the hypothesis that specific markers of biventricular shape may discriminate differences between rTOF patients who did and did not require subsequent PVR better than standard imaging indices. In this cross-sectional retrospective study, biventricular shape models were customized to CMR images from 84 rTOF patients. A statistical atlas of end-diastolic shape was constructed using principal component analysis. Multivariate regression was used to quantify shape mode and imaging index associations with subsequent intervention status (PVR, n = 48 vs. No-PVR, n = 36), while accounting for confounders. Clustering analysis was used to test the ability of the most significant shape modes and imaging indices to discriminate PVR status as evaluated by a Matthews correlation coefficient (MCC). Geometric strain analysis was also conducted to assess shape mode associations with systolic function. PVR status correlated significantly with shape modes associated with right ventricular (RV) apical dilation and left ventricular (LV) dilation (p < 0.01), RV basal bulging and LV conicity (p < 0.05), and pulmonary valve dilation (p < 0.01). PVR status also correlated significantly with RV ejection fraction (p < 0.05) and correlated marginally with LV end-systolic volume index (p < 0.07). Shape modes discriminated subsequent PVR better than standard imaging indices (MCC = 0.49 and MCC = 0.28, respectively) and were significantly associated with RV and LV radial systolic strain. Biventricular shape modes discriminated differences between patients who did and did not require subsequent PVR better than standard imaging indices in current use. These regional features of cardiac morphology may provide insight into adaptive vs. maladaptive types of structural remodeling and point toward an improved quantitative, patient-specific assessment tool for clinical use.

Convolution Neural Network Algorithm for Shockable Arrhythmia Classification Within a Digitally Connected Automated External Defibrillator.

Background Diagnosis of shockable rhythms leading to defibrillation remains integral to improving out-of-hospital cardiac arrest outcomes. New machine learning techniques have emerged to diagnose arrhythmias on ECGs. In out-of-hospital cardiac arrest, an algorithm within an automated external defibrillator is the major determinant to deliver defibrillation. This study developed and validated the performance of a convolution neural network (CNN) to diagnose shockable arrhythmias within a novel, miniaturized automated external defibrillator. Methods and Results There were 26 464 single-lead ECGs that comprised the study data set. ECGs of 7-s duration were retrospectively adjudicated by 3 physician readers (N=18 total readers). After exclusions (N=1582), ECGs were divided into training (N=23 156), validation (N=721), and test data sets (N=1005). CNN performance to diagnose shockable and nonshockable rhythms was reported with area under the receiver operating characteristic curve analysis, F1, and sensitivity and specificity calculations. The duration for the CNN to output was reported with the algorithm running within the automated external defibrillator. Internal and external validation analyses included CNN performance among arrhythmias, often mistaken for shockable rhythms, and performance among ECGs modified with noise to mimic artifacts. The CNN algorithm achieved an area under the receiver operating characteristic curve of 0.995 (95% CI, 0.990-1.0), sensitivity of 98%, and specificity of 100% to diagnose shockable rhythms. The F1 scores were 0.990 and 0.995 for shockable and nonshockable rhythms, respectively. After input of a 7-s ECG, the CNN generated an output in 383±29 ms (total time of 7.383 s). The CNN outperformed adjudicators in classifying atrial arrhythmias as nonshockable (specificity of 99.3%-98.1%) and was robust against noise artifacts (area under the receiver operating characteristic curve range, 0.871-0.999). Conclusions We demonstrate high diagnostic performance of a CNN algorithm for shockable and nonshockable rhythm arrhythmia classifications within a digitally connected automated external defibrillator. Registration URL: https://clinicaltrials.gov/ct2/show/NCT03662802; Unique identifier: NCT03662802.

Sudden cardiac death and malignant arrhythmias: the scope of the problem in adult congenital heart patients.

A key component of recognizing sudden cardiac death (SCD) risk in the adult congenital heart disease (ACHD) patient is the recognition of heart failure risk for each physiology. The risk of SCD is an accrued phenomenon, representing the influences of anatomy, genetics, surgical and catheter interventions, and long-term sequelae of residual hemodynamic issues. These all lead to a substrate for tachyarrhythmia. It is beneficial in thinking about all of the potential combinations of CHD anatomy and physiologies to categorize SCD risk for the ACHD patient in terms of systemic left-ventricular failure, systemic right-ventricular failure, subpulmonary ventricular failure, the dyssynchronous contractility states due to bundle branch block, and single-site ventricular pacing. This article reviews important issues in arrhythmogenesis for ACHD patients with all of these physiologies and discusses potential cardiac rhythm device-management needs.

An Atlas-Based Analysis of Biventricular Mechanics in Tetralogy of Fallot.

The current study proposes an efficient strategy for exploiting the statistical power of cardiac atlases to investigate whether clinically significant variations in ventricular shape are sufficient to explain corresponding differences in ventricular wall motion directly, or if they are indirect markers of altered myocardial mechanical properties. This study was conducted in a cohort of patients with repaired tetralogy of Fallot (rTOF) that face long-term right ventricular (RV) and/or left ventricular (LV) dysfunction as a consequence of adverse remodeling. Features of biventricular end-diastolic (ED) shape associated with RV apical dilation, LV dilation, RV basal bulging, and LV conicity correlated with components of systolic wall motion (SWM) that contribute most to differences in global systolic function. A finite element analysis of systolic biventricular mechanics was employed to assess the effect of perturbations in these ED shape modes on corresponding components of SWM. Perturbations to ED shape modes and myocardial contractility explained observed variation in SWM to varying degrees. In some cases, shape markers were partial determinants of systolic function and, in other cases, they were indirect markers for altered myocardial mechanical properties. Patients with rTOF may benefit from an atlas-based analysis of biventricular mechanics to improve prognosis and gain mechanistic insight into underlying myocardial pathophysiology.

Familial Recurrence Patterns in Congenitally Corrected Transposition of the Great Arteries: An International Study.

BACKGROUND: Congenitally corrected transposition of the great arteries (ccTGA) is a rare disease of unknown cause. We aimed to better understand familial recurrence patterns. METHODS: An international, multicentre, retrospective cohort study was conducted in 29 tertiary hospitals in 6 countries between 1990 and 2018, entailing investigation of 1043 unrelated ccTGA probands. RESULTS: Laterality defects and atrioventricular block at diagnosis were observed in 29.9% and 9.3%, respectively. ccTGA was associated with primary ciliary dyskinesia in 11 patients. Parental consanguinity was noted in 3.4% cases. A congenital heart defect was diagnosed in 81 relatives from 69 families, 58% of them being first-degree relatives, including 28 siblings. The most prevalent defects in relatives were dextro-transposition of the great arteries (28.4%), laterality defects (13.6%), and ccTGA (11.1%); 36 new familial clusters were described, including 8 pedigrees with concordant familial aggregation of ccTGA, 19 pedigrees with familial co-segregation of ccTGA and dextro-transposition of the great arteries, and 9 familial co-segregation of ccTGA and laterality defects. In one family co-segregation of ccTGA, dextro-transposition of the great arteries and heterotaxy syndrome in 3 distinct relatives was found. In another family, twins both displayed ccTGA and primary ciliary dyskinesia. CONCLUSIONS: ccTGA is not always a sporadic congenital heart defect. Familial clusters as well as evidence of an association between ccTGA, dextro-transposition of the great arteries, laterality defects and in some cases primary ciliary dyskinesia, strongly suggest a common pathogenetic pathway involving laterality genes in the pathophysiology of ccTGA.

Time to put the mammillothalamic pathway into context.

The medial diencephalon, in particular the mammillary bodies and anterior thalamic nuclei, has long been linked to memory and amnesia. The mammillary bodies provide a dense input into the anterior thalamic nuclei, via the mammillothalamic tract. In both animal models, and in patients, lesions of the mammillary bodies, mammillothalamic tract and anterior thalamic nuclei all produce severe impairments in temporal and contextual memory, yet it is uncertain why these regions are critical. Mounting evidence from electrophysiological and neural imaging studies suggests that mammillothalamic projections exercise considerable distal influence over thalamo-cortical and hippocampo-cortical interactions. Here, we outline how damage to the mammillary body-anterior thalamic axis, in both patients and animal models, disrupts behavioural performance on tasks that relate to contextual ("where") and temporal ("when") processing. Focusing on the medial mammillary nuclei as a possible 'theta-generator' (through their interconnections with the ventral tegmental nucleus of Gudden) we discuss how the mammillary body-anterior thalamic pathway may contribute to the mechanisms via which the hippocampus and neocortex encode representations of experience.

Computational analysis of cardiac structure and function in congenital heart disease: Translating discoveries to clinical strategies.

Increased availability and access to medical image data has enabled more quantitative approaches to clinical diagnosis, prognosis, and treatment planning for congenital heart disease. Here we present an overview of long-term clinical management of tetralogy of Fallot (TOF) and its intersection with novel computational and data science approaches to discovering biomarkers of functional and prognostic importance. Efforts in translational medicine that seek to address the clinical challenges associated with cardiovascular diseases using personalized and precision-based approaches are then discussed. The considerations and challenges of translational cardiovascular medicine are reviewed, and examples of digital platforms with collaborative, cloud-based, and scalable design are provided.

Transjugular liver biopsy for Fontan associated liver disease surveillance: Technique, outcomes and hemodynamic correlation.

BACKGROUND: Fontan associated liver disease (FALD) is attributed to the limitations of the Fontan circulation, resulting in congestive hepatopathy. The technique and outcomes of transjugular liver biopsies (TJLB) in Fontan patients warrant definition as part of a rigorous FALD surveillance program. METHOD: Four year review of patients with Fontan physiology who underwent a TJLB during surveillance catheterizations. Biopsy site, technique, histology, angiography, hemodynamics, and complications were reviewed to assess correlation of biopsy scores with simultaneously obtained catheterization hemodynamics. RESULTS: 125 patients with a TJLB from 10/1/14 to 5/1/18. Median age 17 years (2-50.5). Technical success 100% (125/125), all samples diagnostic. 17% (21) accessed via the left internal jugular vein, secondary to right IJ occlusion or Heterotaxy syndrome. No patients had superior compartment obstruction preventing transjugular approach. 3.2% complication rate (4/125). Complications were early in the experience, including capsular perforation (2), renal hematoma (1) and hemobilia (1), all without long-term effect and all avoidable. After standardized entry/exit angiography was adopted, no further complications noted. There is a significant correlation between the newly described modified Ishak congestive hepatic fibrosis (ICHF) score with mean Fontan pressure, time from Fontan and cardiac index. CONCLUSIONS: TJLB is an alternate method for obtaining critical FALD surveillance data, with lower complication rates that traditional techniques. Vascular anomalies in Fontan physiology appear common and warrant pre-biopsy assessment. There is a significant correlation between biopsy score, time from Fontan, mean Fontan pressure and cardiac index.