Automatic Prediction of Paediatric Cardiac Output From Echocardiograms Using Deep Learning Models.

Background: Cardiac output (CO) perturbations are common and cause significant morbidity and mortality. Accurate CO assessment is crucial for guiding treatment in anaesthesia and critical care, but measurement is difficult, even for experts. Artificial intelligence methods show promise as alternatives for accurate, rapid CO assessment. Methods: We reviewed paediatric echocardiograms with normal CO and a dilated cardiomyopathy patient group with reduced CO. Experts measured the left ventricular outflow tract diameter, velocity time integral, CO, and cardiac index (CI). EchoNet-Dynamic is a deep learning model for estimation of ejection fraction in adults. We modified this model to predict the left ventricular outflow tract diameter and retrained it on paediatric data. We developed a novel deep learning approach for velocity time integral estimation. The combined models enable automatic prediction of CO. We evaluated the models against expert measurements. Primary outcomes were root-mean-squared error, mean absolute error, mean average percentage error, and coefficient of determination (R2). Results: In a test set unused during training, CI was estimated with the root-mean-squared error of 0.389 L/min/m2, mean absolute error of 0.321 L/min/m2, mean average percentage error of 10.8%, and R2 of 0.755. The Bland-Altman analysis showed that the models estimated CI with a bias of +0.14 L/min/m2 and 95% limits of agreement -0.58 to 0.86 L/min/m2. Conclusions: Our model estimated CO with strong correlation to ground truth and a bias of 0.17 L/min, better than many CO measurements in paediatrics. Model pretraining enabled accurate estimation despite a small dataset. Potential uses include supporting clinicians in real-time bedside calculation of CO, identification of low-CO states, and treatment responses.

Contexte: Les perturbations du débit cardiaque sont fréquentes et associées à des taux élevés de morbidité et de mortalité. Une évaluation juste du débit cardiaque est essentielle pour orienter le choix du traitement anesthésique et des soins critiques. Or, il est difficile de mesurer le débit cardiaque, même pour les experts. Les méthodes fondées sur l'intelligence artificielle semblent toutefois prometteuses pour évaluer le débit cardiaque avec exactitude et rapidité. Méthodologie: Nous avons analysé des échocardiogrammes pédiatriques chez des personnes dont le débit cardiaque est normal ainsi que chez des patients qui étaient atteints d'une cardiomyopathie dilatée et dont le débit cardiaque était réduit. Des experts ont mesuré le diamètre de la voie d'éjection ventriculaire gauche, l'intégrale de la vitesse par rapport au temps (IVT), le débit cardiaque et l'index cardiaque. L'outil EchoNet-Dynamic est un modèle d'apprentissage profond qui donne une estimation de la fraction d'éjection chez les adultes. Nous avons modifié ce modèle afin qu'il puisse prédire le diamètre de la voie d'éjection ventriculaire gauche et l'avons entraîné à l'aide de données pédiatriques. Nous avons également mis au point une nouvelle approche d'apprentissage profond pour l'estimation des valeurs d'IVT. La combinaison de ces modèles a permis de prédire de façon automatique le débit cardiaque, et nous avons évalué les résultats obtenus par rapport à ceux des experts. Les principaux critères d'évaluation étaient l'erreur moyenne quadratique (EMQ), l'erreur moyenne absolue (EMA), le pourcentage d'erreur moyen (PEM) ainsi que le coefficient de détermination (R2). Résultats: Dans un ensemble d'essais n'ayant pas été utilisé au cours de l'entraînement du modèle, l'index cardiaque a été estimé avec une EMQ de 0,389 L/min/m2, une EMA de 0,321 L/min/m2, un PEM de 10,8 % et un R2 de 0,755. Selon l'analyse de Bland-Altman, le biais pour les estimations de l'index cardiaque était de + 0,14 L/min/m2, et les limites de concordance à 95 % étaient de ­0,58 à 0,86 L/min/m2. Conclusions: Les estimations générées par le modèle pour le débit cardiaque montraient une forte corrélation avec les valeurs de référence et un biais à 0,17 L/min, ce qui est mieux que bien des mesures du débit cardiaque utilisées en pédiatrie. Malgré un petit ensemble de données, le modèle entraîné a permis de produire une estimation juste. Les utilisations potentielles comprennent l'aide aux cliniciens dans le calcul du débit cardiaque en temps réel et au chevet du patient, le dépistage d'un faible débit cardiaque et l'évaluation de la réponse au traitement.

Diastolic myocardial mechanics and their relation to ventricular filling pressures and postoperative course in functionally single ventricles.

Diastolic dysfunction affects clinical outcomes in patients with a functionally single ventricle (FSV). The objective of this work is to study the association of ventricular mechanics and interventricular dependence on diastolic parameters and early post-Fontan outcomes. Sixty-one patients with FSV underwent echocardiography, cardiac catheterization, and magnetic resonance imaging on the same day before or after the Fontan procedure. Echocardiographic diastolic parameters, ventricular mass, and incoordinate wall motion, defined by the number of dyskinetic segments or by the lateral wall delay, were determined and studied for relationships with invasively measured hemodynamics and early postoperative Fontan course. In subjects with a sizable secondary ventricle, incoordinate motion was additionally analyzed at the left- and right-sided ventricular free walls. Resting ventricular end-diastolic pressure (VEDP) was ≤10 mmHg in most subjects. Individual echocardiographic parameters of the diastolic flow and tissue velocities did not correlate with VEDP, other hemodynamics, or post-Fontan clinical course. Incoordinate wall motion in the dominant and in the sizeable secondary ventricle, defined by the lateral wall delay or by the number of dyskinetic segments, was the only echo parameter that correlated, albeit weakly, with VEDP (r = 0.247, P = 0.040), oxygen saturation (r = -0.417, P = 0.001), pulmonary vascular resistance and flow (Qp) (r = -0.303, P = 0.011), Fontan fenestration flow (r = 0.512, P = 0.009), and duration of endotracheal intubation (r = 0.292, P = 0.022). When the nondominant (secondary) ventricle was accounted for in the analysis of incoordinate wall motion, these associations strengthened. The degree of incoordinate ventricular wall motion in diastole was associated with VEDP and postoperative Fontan course in FSV. Analysis of incoordinate wall motion of the dominant and sizeable secondary ventricle may be warranted and should be included in the assessment of the FSV after the Fontan procedure.NEW & NOTEWORTHY Diastolic dysfunction affects outcomes in patients with functionally single ventricles (FSVs) but is difficult to assess. We found that incoordinate wall motion was the only echo parameter that correlated with FSV end-diastolic pressure, oxygen saturation, pulmonary vascular resistance and flow, and duration of endotracheal intubation. Analysis of incoordinate wall motion in the nondominant (secondary) ventricle strengthened these associations. Analyzing incoordinate wall motion should be included in the assessment of the FSV after the Fontan procedure.

Local arterial stiffness measured by ultrafast ultrasound imaging in childhood cancer survivors treated with anthracyclines.

Background: There is conflicting literature regarding the long-term effect of anthracycline treatment on arterial stiffness. This study assessed local arterial stiffness using ultrafast ultrasound imaging (UUI) in anthracycline treated childhood cancer survivors, at rest and during exercise. Methods: 20 childhood cancer survivors (mean age 21.02 ± 9.45 years) treated with anthracyclines (mean cumulative dose 200.7 ± 126.80 mg/m2) and 21 healthy controls (mean age 26.00 ± 8.91 years) were included. Participants completed a demographic survey, fasting bloodwork for cardiovascular biomarkers, and performed a submaximal exercise test on a semi-supine bicycle. Pulse wave velocity (PWV) was measured in the left common carotid artery by direct pulse wave imaging using UUI at rest and submaximal exercise. Both PWV at the systolic foot (PWV-SF) and dicrotic notch (PWV-DN) were measured. Central (carotid-femoral) PWV was obtained by applanation tonometry. Carotid measurements were taken by conventional ultrasound. Measures were compared using two-tailed Students t-test or Chi-squared test, as appropriate. Results: There was no statistically significant difference (p > 0.05) between childhood cancer survivors and healthy controls in demographic parameters (age, sex, weight, height, BMI), blood biomarkers (total cholesterol, triglycerides, LDL-c, HDL-c, hs-CRP, fasting glucose, insulin, Hb A1c), cardiovascular parameters (intima media thickness, systolic and diastolic blood pressure, heart rate, carotid diameters, distensibility) or PWV measured by UUI at rest or at exercise. There was also no difference in the cardiovascular adaptation between rest and exercise in the two groups (p > 0.05). Multivariate analysis revealed age (p = 0.024) and LDL-c (p = 0.019) to be significant correlates of PWV-SF in childhood cancer survivors, in line with previously published data. Conclusion: We did not identify a significant impact of anthracycline treatment in young survivors of childhood cancer on local arterial stiffness in the left common carotid artery as measured by UUI.

Impact of Ventricular Geometric Characteristics on Myocardial Stiffness Assessment Using Shear-Wave Velocity in Healthy Children and Young Adults.

BACKGROUND: Diastolic myocardial stiffness (MS) can serve as a key diagnostic parameter for congenital or acquired heart diseases. Using shear modulus and shear-wave velocity (SWV), shear-wave elastography (SWE) is an emerging ultrasound-based technique that can allow noninvasive assessment of MS. However, MS extrinsic parameters such as left ventricular geometric characteristics could affect shear-wave propagation. The aims of this study were to determine a range of normal values of MS using SWE in age groups of healthy children and young adults and to explore the impact of left ventricular geometric characteristics on SWE. METHODS: Sixty healthy volunteers were recruited in the study and divided into 2 groups: neonates (0-1 months old, n = 15) and >1 month old (1 month to 45 years of age, n = 45). SWE was performed using the Verasonics Vantage systems with a phased-array ultrasound probe. The anteroseptal basal segment was assessed in two views. SWE was electrocardiographically triggered during the end-diastolic phase. Conventional echocardiography was performed to assess ventricular function and anatomy. Results are presented as stiffness values along with mean velocity measurements and SDs. Simple and multivariate linear regression analyses were performed. RESULTS: For neonates, mean MS was 1.87 ± 0.79 kPa (range, 0.59-2.91 kPa; mean SWV, 1.37 ± 0.57 m/sec), with high variability and no correlation with age (P = .239). For this age group, no statistically significant correlation was found between MS and any demographic or echocardiographic parameters (P > .05). For the >1 month old group, a mean MS value of 1.67 ± 0.53 kPa was observed (range, 0.6-3 kPa; mean SWV, 1.29 ± 0.49 m/sec) for healthy volunteers. When paired for age, no sex-related difference was observed (P = .55). In univariate linear regression analysis, age (r = 0.83, P < .01), diastolic interventricular septal thickness (r = 0.72, P < .01), and left ventricular end-diastolic diameter (r = 0.67, P < .01) were the parameters with the highest correlation coefficients with MS. In a multiple linear regression analysis incorporating these three parameters as cofounding factors, age was the only statistically significant parameters (r = 0.81, P = .02). CONCLUSION: Diastolic MS increases linearly in children and young adults. Diastolic MS correlates more robustly with age than with myocardial and left ventricular geometric characteristics. However, the geometry affects SWV, implying the need to determine well-established boundaries in future studies for the clinical application of SWE.

Right Ventricular Electromechanical Dyssynchrony and Its Relation to Right Ventricular Remodeling, Dysfunction, and Exercise Capacity in Ebstein Anomaly.

BACKGROUND: Abnormal atrioventricular and intraventricular electrical conduction and dysfunction of the functional right ventricle (fRV) are common in Ebstein anomaly (EA). However, fRV mechanical dyssynchrony and its relation to fRV function are poorly characterized. We evaluated fRV mechanical dyssynchrony in EA patients in relation to fRV remodeling, dysfunction, and exercise intolerance. METHODS: We retrospectively analyzed data from nonoperated EA patients and age-matched controls who underwent echocardiography, cardiovascular magnetic resonance imaging, and cardiopulmonary exercise testing to quantify right ventricular (RV) remodeling, dysfunction, and exercise capacity. The relation of these to fRV dyssynchrony was retrospectively investigated. Right ventricular mechanical dyssynchrony was defined by early fRV septal activation (right-sided septal flash), RV lateral wall prestretch/late contraction, postsystolic shortening, and intra-RV delay using two-dimensional strain echocardiography. The SD of time to peak shortening among the fRV segments was calculated as a parameter of mechanical dispersion. RESULTS: Thirty-five EA patients (10 of whom were <18 years of age) and 35 age-matched controls were studied. Ebstein anomaly patients had worse RV function and increased intra-RV dyssynchrony versus controls. Nineteen of 35 (54%) EA patients had early septal activation with simultaneous stretch and consequent late activation and postsystolic shortening of RV lateral segments. Intra-fRV mechanical delay correlated with fRV end-diastolic volume index (r = 0.43, P < .05) and fRV end-systolic volume index (r = 0.63, P < .001). The fRV ejection fraction was lower in EA with versus without right-sided septal flash (44.9 ± 11.0 vs 54.2 ± 8.2, P = .012). The fRV mechanical dispersion correlated with the percentage of predicted peak VO2 (r = -0.35, P < .05). CONCLUSIONS: In EA, fRV mechanical dyssynchrony is associated with fRV remodeling, dysfunction, and impaired exercise capacity. Mechanical dyssynchrony as a therapeutic target in selected EA patients warrants further study.

Reversal of right ventricular pressure loading improves biventricular function independent of fibrosis in a rabbit model of pulmonary artery banding.

Right ventricular (RV) pressure loading leads to RV and left ventricular (LV) dysfunction through RV hypertrophy, dilatation and fibrosis. Relief of RV pressure load improves RV function. However, the impact and mechanisms on biventricular reverse-remodelling and function are only partially characterized. We evaluated the impact of RV pressure overload relief on biventricular remodelling and function in a rabbit model of reversible pulmonary artery banding (PAB). Rabbits were randomized to three groups: (1) Sham-operated controls (n = 7); (2) PAB (NDef, n = 7); (3) PAB followed by band deflation (Def, n = 5). Sham and NDef animals were sacrificed at 6 weeks after PAB surgery. Def animals underwent PAB deflation at 6 weeks and sacrifice at 9 weeks. Biventricular geometry, function, haemodynamics, hypertrophy and fibrosis were compared between groups using echocardiography, magnetic resonance imaging, high-fidelity pressure-tipped catheters and histology. RV pressure loading caused RV dilatation, systolic dysfunction, myocyte hypertrophy and LV compression which improved after PAB deflation. RV end-diastolic pressure (RVEDP) decreased after PAB deflation, although remaining elevated vs. Sham. LV end-diastolic pressure (LVEDP) was unchanged following PAB deflation. RV and LV collagen volumes in the NDef and Def group were increased vs. Sham, whereas RV and LV collagen volumes were similar between NDef and Def groups. RV myocyte hypertrophy (r = 0.75, P < 0.001) but not collagen volume was related to RVEDP. LV myocyte hypertrophy (r = 0.58, P = 0.016) and collagen volume (r = 0.56, P = 0.031) correlated with LVEDP. In conclusion, relief of RV pressure overload improves RV and LV geometry, hypertrophy and function independent of fibrosis. The long-term implications of persistent fibrosis and increased biventricular filling pressures, even after pressure load relief, need further study. KEY POINTS: Right ventricular (RV) pressure loading in a pulmonary artery banding rabbit model is associated with RV dilatation, left ventricular (LV) compression; biventricular myocyte hypertrophy, fibrosis and dysfunction. The mechanisms and impact of RV pressure load relief on biventricular remodelling and function has not been extensively studied. Relief of RV pressure overload improves biventricular geometry in conjunction with improved RV myocyte hypertrophy and function independent of reduced fibrosis. These findings raise questions as to the importance of fibrosis as a therapeutic target.

Longitudinal Changes in Cardiac Structure and Function in Pediatric Kidney Transplant Recipients.

BACKGROUND: Cardiovascular disease results in increased morbidity and mortality in pediatric kidney transplant recipients. Longitudinal changes in cardiac structure and function and the association with blood pressure control over time in pediatric kidney transplant recipients are unknown. METHODS: To determine the influence of blood pressure control on cardiac changes following pediatric kidney transplant, we conducted a retrospective cohort study of children who received their first kidney transplant at the Hospital for Sick Children from 2004 to 2015. Children were followed until transfer to adult care or censoring in July 2018. Cardiac structure and function parameters were collected from clinical echocardiograms and assessed using standardized scores. Blood pressure control was determined by systolic blood pressure Z scores (above or below the 90th percentile) in combination with antihypertensive medications. A segmented mixed-effects model assessed Z scores of interventricular septum thickness, left ventricular end-diastolic dimension, and left ventricular posterior wall dimension. RESULTS: Of 142 children included, 58% were men, mean age at transplant was 11 (±4.5) years, and average follow-up time was 4 (±3) years. All cardiac structural Z scores improved during follow-up. Interventricular septum thickness normalized at 4.0 years post-transplant. Left ventricular end-diastolic dimension normalized at 1.5 years post-transplant. Left ventricular posterior wall dimension normalized at 6.3 years post-transplant. Left ventricular mass index showed sustained improvement up to 12 years post-transplant. Individuals with uncontrolled blood pressure had increased left ventricular mass (ß=2.97 [95% CI, 0.77-5.16]). CONCLUSIONS: Cardiac structural abnormalities improve following kidney transplantation and normalize within 7 years, especially with controlled blood pressure. Strict blood pressure control is critical after pediatric kidney transplantation.

Retraining an Artificial Intelligence Algorithm to Calculate Left Ventricular Ejection Fraction in Pediatrics.

OBJECTIVES: Identifying patients with low left ventricular ejection fraction (LVEF) and monitoring LVEF responses to treatment are important clinical goals. Can a deep-learning algorithm predict pediatric LVEF within clinically acceptable error? DESIGN: The study authors wanted to fine-tune an adult deep-learning algorithm to calculate LVEF in pediatric patients. A priori, their objective was to refine the algorithm to perform LVEF calculation with a mean absolute error (MAE) ≤5%. SETTING: A quaternary pediatric hospital PARTICIPANTS: A convenience sample (n = 321) of echocardiograms from newborns to 18 years old with normal cardiac anatomy or hemodynamically insignificant anomalies. Echocardiograms were chosen from a group of healthy controls with known normal LVEF (n = 267) and a dilated cardiomyopathy patient group with reduced LVEF (n = 54). INTERVENTIONS: The artificial intelligence model EchoNet-Dynamic was tested on this data set and then retrained, tested, and further validated to improve LVEF calculation. The gold standard value was LVEF calculated by clinical experts. MEASUREMENTS AND MAIN RESULTS: In a random subset of subjects (n = 40) not analyzed prior to selection of the final model, EchoNet-Dynamic calculated LVEF with a MAE of 8.39%, R2 = 0.47 without, and MAE 4.47%, R2 = 0.87 with fine-tuning. Bland-Altman analysis suggested that the model slightly underestimates LVEF (bias = -2.42%). The 95% limits of agreement between actual and calculated values were -12.32% to 7.47%. CONCLUSIONS: The fine-tuned model calculates LVEF in a range of pediatric patients within clinically acceptable error. Potential advantages include reducing operator error in LVEF calculation and supporting independent LVEF assessment by inexperienced users.

Regional Vascular Changes and Aortic Dilatation in Pediatric Patients With Bicuspid Aortic Valve.

BACKGROUND: Bicuspid aortic valve (BAV) is the most common congenital heart disease, often associated with valve dysfunction, coarctation of the aorta, and ascending aorta dilatation. Aortic dilatation might result from abnormal regional hemodynamics or inherent vascular disease. Vascular function in pediatric BAV remains poorly characterized. METHODS: A cross-sectional study was performed to evaluate vascular function in 142 children with BAV aged 7-18 years compared with healthy control children. Echocardiography was performed to assess aortic dimensions, BAV function, and vascular function (aortic arch pulse wave velocity [PWV]), carotid intima media thickness, and aortic stiffness and distensibility). Carotid-femoral and carotid-radial PWV were assessed using tonometry. Vascular function was compared for 4 patient groups stratified according to aortic dilatation and a history of coarctation of the aorta. Multivariate regression analysis was performed to determine predictors of aortic dilatation. RESULTS: Children with BAV had stiffer and less distensible ascending aortas with higher aortic arch PWV compared with control children. Carotid-femoral and carotid-radial PWV were not increased in patients with BAV, and the vascular assessment of the abdominal aorta was unremarkable. Multivariate regression revealed that aortic arch PWV was the only vascular function parameter that was associated with aortic dilatation. CONCLUSIONS: Children with BAV have differences in vascular function that are confined to their proximal aorta, even in normal functioning BAV. The observed differences in vascular function are likely multifactorial, with contributions from abnormal regional flow and a potential localized primary aortopathy.

Machine-learning-based exploration to identify remodeling patterns associated with death or heart-transplant in pediatric-dilated cardiomyopathy.

AIMS: We investigated left ventricular (LV) remodeling, mechanics, systolic and diastolic function, combined with clinical characteristics and heart-failure treatment in association to death or heart-transplant (DoT) in pediatric idiopathic, genetic or familial dilated cardiomyopathy (DCM), using interpretable machine-learning. METHODS AND RESULTS: Echocardiographic and clinical data from pediatric DCM and healthy controls were retrospectively analyzed. Machine-learning included whole cardiac-cycle regional longitudinal strain, aortic, mitral and pulmonary vein Doppler velocity traces, age and body surface area. We used unsupervised multiple kernel learning for data dimensionality reduction, positioning patients based on complex conglomerate information similarity. Subsequently, k-means identified groups with similar phenotypes. The proportion experiencing DoT was evaluated. Pheno-grouping identified 5 clinically distinct groups that were associated with differing proportions of DoT. All healthy controls clustered in groups 1 to 2, while all, but one, DCM subjects, clustered in groups 3 to 5; internally validating the algorithm. Cluster-5 comprised the oldest, most medicated patients, with combined systolic and diastolic heart-failure and highest proportion of DoT. Cluster-4 included the youngest patients characterized by severe LV remodeling and systolic dysfunction, but mild diastolic dysfunction and the second-highest proportion of DoT. Cluster-3 comprised young patients with moderate remodeling and systolic dysfunction, preserved apical strain, pronounced diastolic dysfunction and lowest proportion of DoT. CONCLUSIONS: Interpretable machine-learning, using full cardiac-cycle systolic and diastolic data, mechanics and clinical parameters, can potentially identify pediatric DCM patients at high-risk for DoT, and delineate mechanisms associated with risk. This may facilitate more precise prognostication and treatment of pediatric DCM.

Asymmetric Regional Work Contributes to Right Ventricular Fibrosis, Inefficiency, and Dysfunction in Pulmonary Hypertension versus Regurgitation.

BACKGROUND: Right ventricular (RV) pressure loading from pulmonary hypertension (PH) and volume loading from pulmonary regurgitation (PR) lead to RV dysfunction, a critical determinant of clinical outcomes, but their impact on regional RV mechanics and fibrosis is poorly characterized. The aim of this study was to test the hypothesis that regional myocardial mechanics and efficiency in RV pressure and volume loading are associated with RV fibrosis and dysfunction. METHODS: Eight PH, six PR, and five sham-control rats were studied. The PH rat model was induced using Sugen5416, a vascular endothelial growth factor receptor 2 inhibitor, combined with chronic hypoxia. PR rats were established by surgical laceration of the pulmonary valve leaflets. Six (n = 4) or 9 (n = 4) weeks after Sugen5416 and hypoxia and 12 weeks after PR surgery, myocardial strain and RV pressure were measured and RV pressure-strain loops generated. We further studied RV regional mechanics in 11 patients with PH. Regional myocardial work was calculated as the pressure-strain loop area (mm Hg ∙ %). Regional myocardial work efficiency was quantified through wasted work (ratio of systolic lengthening to shortening work). The relation of regional myocardial work to RV fibrosis and dysfunction was analyzed. RESULTS: In rats, PH and PR induced similar RV dilatation, but fractional area change (%) was lower in PH than in PR. RV lateral wall work was asymmetrically higher in PH compared with sham, while septal work was similar to sham. In PR, lateral and septal work were symmetrically higher versus sham. Myocardial wasted work ratio was asymmetrically increased in the PH septum versus sham. Fibrosis in the RV lateral wall, but not septum, was higher in PH than PR. RV fibrosis burden was linearly related to regional work and to measures of RV systolic and diastolic function but not to wasted myocardial work ratio. Patients with PH demonstrated similar asymmetric and inefficient regional myocardial mechanics. CONCLUSIONS: Asymmetric RV work and increased wasted septal work in experimental PH are associated with RV fibrosis and dysfunction. Future investigation should examine whether assessment of asymmetric regional RV work and efficiency can predict clinical RV failure and influence patient management.

Pulmonary artery banding is a relevant model to study the right ventricular remodeling and dysfunction that occurs in pulmonary arterial hypertension.

Right ventricular (RV) dysfunction determines mortality in patients with pulmonary arterial hypertension (PAH) and RV pressure loading. Experimental models commonly use Sugen hypoxia (SuHx)-induced PAH, monocrotaline (MCT)-induced PAH, or pulmonary artery banding (PAB). Because PAH models cannot interrogate RV effects or therapies independent of pulmonary vascular effects, we aimed to compare RV function and fibrosis in experimental PAB vs. PAH. Thirty rats were randomized to either sham controls, PAB, SuHx-, or MCT-induced PAH. RV pressures and function were assessed by high-fidelity pressure-tipped catheters and by echocardiography. RV myocyte hypertrophy, fibrosis, and capillary density were quantified from hematoxylin-eosin, picrosirius red-stained, and CD31-immunostained RV sections, respectively. RV pressures and the RV-to-left ventricular pressure ratio were significantly increased in all three groups to a similar degree (PAB 65 ± 17 mmHg, SuHx 72 ± 16 mmHg, and MCT 70 ± 12 mmHg) vs. controls (23 ± 2 mmHg, all P < 0.01). RV dilatation, hypertrophy, and fibrosis were similarly increased, and capillary density decreased, in the three models (RV fibrosis; PAB 13.3 ± 3.6%, SuHx 9.8 ± 3.0% and MCT 10.9 ± 2.4% vs control 5.5 ± 1.1%, all P < 0.05). RV function was similarly decreased in all models vs. controls. We observed comparable RV dilatation, hypertrophy, systolic and diastolic dysfunction, fibrosis, and capillary rarefaction in rat models of PAB, SuHx-, and MCT-induced PAH. These results suggest that PAB, when sufficiently severe, induces features of maladaptive RV remodeling and can be used to investigate RV pathophysiology and therapy effects independent of pulmonary vascular resistance.NEW & NOTEWORTHY Although animal models of pulmonary arterial hypertension and pressure loading are important to study right ventricular (RV) pathophysiology, pulmonary arterial hypertension models cannot interrogate RV responses independent of pulmonary vascular effects. Comparing three commonly used rat models under similar elevated RV pressure, we found that all models resulted in comparable maladaptive RV remodeling and dysfunction. Thus, these findings suggest that the pulmonary artery banding model can be used to investigate mechanisms of RV dysfunction in RV pressure overload and the effect of potential therapies.

New Comprehensive Reference Values for Arterial Vascular Parameters in Children.

BACKGROUND: Noninvasive measurements of vascular parameters can be used for the detection and risk stratification of cardiovascular diseases. Most vascular parameters are influenced by age and body size, but pediatric reference values are scarce and limited to a few parameters. The aim of this study was to develop pediatric reference values and Z score equations for a comprehensive set of vascular parameters. METHODS: A total of 292 healthy subjects aged 0 to 18 years were prospectively recruited. Stiffness index ß, pressure-strain elastic modulus, common carotid intima-media thickness, brachial flow-mediated dilation, radial augmentation index, central and right arm peripheral artery pulse-wave velocities, and pulse-wave velocity ratio were assessed. Normalization for age and anthropometric variables was performed using parametric multivariate regression modeling. Z scores were assessed for heteroscedasticity, residual association with age and body size, and distribution. RESULTS: Multivariate regression models with various combinations of height, weight, and age were used to obtain Z scores that were independent of age and body size. There was no residual association between Z scores and body size, age, or body mass index. There was no significant departure from the normal distribution. CONCLUSIONS: The authors present reference values and Z score equations for a comprehensive set of vascular parameters during childhood. Further studies are necessary to assess their usefulness in detecting the vascular signs of subclinical atherosclerosis and chronic diseases, including congenital heart disease.

The right ventricular myocardial systolic-to-diastolic duration ratio in children after surgical repair of Tetralogy of Fallot.

Right ventricular (RV) function impacts clinical outcomes after surgical repair of Tetralogy of Fallot (rTOF). However, assessment of RV function remains difficult. We investigated the RV myocardial systolic-to-diastolic (S/D) duration ratio derived from strain imaging time intervals to characterize RV myocardial performance, exploring its relation with peak oxygen consumption during exercise (V̇o2) and cardiac magnetic resonance-derived RV dilation and function in rTOF. We retrospectively analyzed 76 children with rTOF and 42 normal controls. The RV myocardial S/D duration ratio was measured from RV global and regional 2D speckle tracking longitudinal strain. Time from QRS onset to peak systolic strain was defined as the systolic duration. The S/D duration ratio was calculated and corrected for heart rate (HR). Postsystolic shortening (PSS) duration was defined as shortening time after cessation of pulmonary systolic antegrade flow. The RV myocardial S/D duration ratio, corrected or uncorrected for HR, was significantly higher in rTOF vs. controls (1 ± 0.3 vs. 0.8 ± 0.2, P = 0.004) in relation to prolonged PSS. The HR-corrected myocardial S/D duration ratio correlated weakly with RV ejection fraction (EF, r = -0.37, P = 0.001) and V̇o2 (r = -0.32, P = 0.042). In multiregression analysis, RV EF was independently associated with the myocardial S/D duration ratio. The RV myocardial S/D duration ratio is a parameter of RV myocardial performance and efficiency, incorporating elements of systolic and diastolic performance, mechanical dyssynchrony, and PSS. The S/D duration ratio is associated with exercise capacity and RV dysfunction in rTOF.NEW & NOTEWORTHY This is the first study to assess right ventricular myocardial performance using the systolic-to-diastolic duration ratio derived from 2D strain. Seventy-six children with repaired Tetralogy of Fallot were evaluated. Echocardiographic data were correlated with cardiac magnetic resonance and peak oxygen consumption during exercise. The results show the right ventricular myocardial systolic-to-diastolic duration ratio incorporates systolic and diastolic performance, electromechanical dyssynchrony, and postsystolic shortening and is associated with exercise capacity in repaired Tetralogy of Fallot.

Echocardiographic Assessment of Cardiac Function in Pediatric Survivors of Anthracycline-Treated Childhood Cancer.

BACKGROUND: Anthracycline-induced cardiotoxicity is a major cause of morbidity and mortality in childhood cancer survivors (CCSs). Echocardiographic myocardial strain imaging is recommended in adult patients with cancer, but its role in pediatric CCSs has not been well established. Aims of this study were to determine the prevalence of abnormalities in left ventricular strain in pediatric CCSs, to compare strain with other echocardiographic measurements and blood biomarkers, and to explore risk factors for reduced strain. METHODS: CCSs ≥3 years from their last anthracycline treatment were enrolled in this multicenter study and underwent a standardized functional echocardiogram and biomarker collection. Regression analysis was used to identify factors associated with longitudinal strain (LS). RESULTS: Five hundred forty-six pediatric CCSs were compared with 134 healthy controls. Abnormal left ventricular ejection fraction (<50%) and mean LS (Z score, <-2) was found in 0.8% and 7.7% of the CCSs, respectively. LS was significantly lower in CCSs than in controls, but the absolute difference was small (0.7%). Lower LS in CCSs was associated with older current age and higher body surface area. Sex, cumulative anthracycline dose, radiotherapy, and biomarkers were not independently associated with LS. Circumferential strain, diastolic parameters, and biomarkers were not significantly different in pediatric CCSs. CONCLUSIONS: Global systolic function and LS are only mildly reduced in pediatric CCSs, and most LS values are within normal range. This makes single LS measurements of limited added value in identifying CCSs at risk for cardiac dysfunction. The utility of strain imaging in the long-term follow-up of CCS remains to be demonstrated.

Right Ventricular Diastolic Function and Right Atrial Function and Their Relation With Exercise Capacity in Ebstein Anomaly.

BACKGROUND: Right ventricular (RV) diastolic function and right atrial (RA) function are poorly characterized in patients with Ebstein anomaly (EA) but may influence functional capacity. We aimed to evaluate RV diastolic function and RA function in EA and study their relationship with biventricular systolic function and exercise capacity. METHODS: Seventy-two patients with EA and 69 controls prospectively underwent echocardiography, cardiovascular magnetic resonance imaging, and cardiopulmonary exercise testing to investigate RV systolic and diastolic function, RA function, and exercise capacity. RESULTS: Altered RV diastolic function was indicated by the reduced tricuspid valve E/A ratio, percentage RV filling time, and early and late diastolic strain rate; and by the increased tricuspid valve E/E', isovolumic relaxation time, and RV myocardial performance index. The average of 6-RV-segment early diastolic strain rate correlated modestly with peak VO2 (r = 0.38, P < 0.01), RV ejection fraction (r = 0.41, P < 0.01), and left ventricular ejection fraction (r = 0.33, P < 0.05). Patients with EA had impaired RA reservoir, conduit, and pump function, which were associated with peak VO2 (r = 0.54, P < 0.001 for reservoir function). CONCLUSIONS: Altered RV diastolic function and RA function in patients with EA are associated with impaired biventricular systolic function and exercise capacity. The stronger correlation of RA vs RV function with exercise capacity suggests that it may be important to evaluate RA function in this population.

Association of Echocardiographic Parameters of Right Ventricular Remodeling and Myocardial Performance With Modified Task Force Criteria in Adolescents With Arrhythmogenic Right Ventricular Cardiomyopathy.

BACKGROUND: The usefulness of echocardiographic indices, including those already used by modified Task Force Criteria (mTFC), and others such as strain imaging, to identify arrhythmogenic right ventricular cardiomyopathy (ARVC) in adolescence is not well established. METHODS: Echocardiograms from 120 adolescents investigated for ARVC (13±4 years) were retrospectively analyzed. According to the mTFC, patients were classified into definite (n=38), borderline (n=39), or possible (n=43) ARVC. Results were compared with 35 healthy controls. mTFC echocardiographic parameters were analyzed, as well as comprehensive right ventricular (RV) and left ventricular assessment of function including parameters not included in mTFC such as pulsed-wave tissue Doppler and RV 2-dimensional speckle strain. RESULTS: mTFC parameters indexed for body surface area were significantly more abnormal in patients with possible, borderline, or definite ARVC compared with controls for parasternal long-axis view of the RV outflow tract. RV end-diastolic diameters were significantly larger in patients versus controls, a difference that increased with likelihood of ARVC. Left ventricular ejection fraction, tricuspid annular peak systolic excursion, and systolic and diastolic pulsed-wave tissue Doppler imaging indices were similar to controls for all groups. Average and segmental RV peak longitudinal systolic strain was significantly lower in patients with definite ARVC (-21±4%) and disease subgroups versus controls (-25±3%). Multivariable risk analysis showed that reduced RV strain was significantly associated with ARVC diagnosis and its likelihood (multivariable odds ratio [95% CI]=1.23 [1.1-1.37]; P<0.001) as was increased end-diastolic diameter at the apical third of the RV (multivariable odds ratio [95% CI]=1.51 [1.33-1.72]; P<0.001). CONCLUSIONS: mTFC echocardiographic criteria are significantly different between patients and controls and between the different diagnostic groups. However, in our cohort, current echocardiographic mTFC are not met by the majority of adolescent ARVC patients, particularly when indexed to body surface area. Measurement of RV apical dimensions and strain may increase the diagnostic yield of echocardiography for ARVC.

Increased Arterial Stiffness Adversely Affects Left Ventricular Mechanics in Patients With Pediatric Takayasu Arteritis From a Toronto Cohort.

BACKGROUND/OBJECTIVE: Takayasu arteritis (TA) is characterized by extensive aortic, large and midsize arterial wall inflammation. The aim of this study was to assess the morphological and elastic properties of the aorta and large arteries and the impact on left ventricular (LV) mechanics in children with TA. METHODS: Seven pediatric TA patients (6 female patients, 13.8 ± 3.2 years) were assessed with magnetic resonance imaging, vascular ultrasound, applanation tonometry, and echocardiography from February 2015 until July 2017 and compared with 7 age- and sex-matched controls. Takayasu arteritis disease activity was assessed clinically by the Pediatric Vasculitis Activity Score (PVAS). RESULTS: Pediatric TA patients showed increased carotid-to-radial artery pulse wave velocity (8.1 ± 1.8 vs. 6.4 ± 0.6 m/s, p = 0.03) and increased carotid-to-femoral artery pulse wave velocity (8.3 ± 1.9 vs. 5.1 ± 0.8 m/s, p < 0.01) when compared with controls. Patients demonstrated increased LV mass index (74.3 ± 18.8 vs. 56.3 ± 10.9 g/m, p = 0.04), altered myocardial deformation with increased basal rotation (-9.8 ± 4.5 vs. -4.0 ± 2.0 degrees, p = 0.01) and torsion (19.9 ± 8.1 vs. 9.1 ± 3.1 degrees, p = 0.01), and impaired LV diastolic function with decreased mitral valve E/A ratio (1.45 ± 0.17 vs. 2.40 ± 0.84, p = 0.01), increased mitral valve E/E' ratio (6.8 ± 1.4 vs. 4.9 ± 0.7, p < 0.01), and increased pulmonary vein A-wave velocity (26.7 ± 5.7 vs. 16.8 ± 3.3 cm/s, p = 0.03). Carotid-to-radial artery pulse wave velocity was associated with systolic (R = 0.94, p < 0.01), diastolic (R = 0.85, p = 0.02), and mean blood pressure (R = 0.91, p < 0.01), as well as disease activity by PVAS (R = 0.75, p = 0.05). The PVAS was associated with carotid-to-radial artery pulse wave velocity (R = 0.75, p = 0.05), as well as systolic (R = 0.84, p = 0.02), diastolic (R = 0.82, p = 0.03), and mean blood pressure (R = 0.84, p = 0.02). CONCLUSIONS: Increased arterial stiffness is present in pediatric TA patients and associated with increased blood pressure and TA disease activity. Pediatric TA patients demonstrate altered LV mechanics, LV hypertrophy, and impaired diastolic function.

Effect of Obstructive Sleep Apnea on Cardiovascular Function in Obese Youth.

The increasing prevalence of overweight or obese children and adolescents is a significant global health concern. Although the effect of obesity on cardiovascular function has been investigated, little is known on the impact of associated obstructive sleep apnea (OSA) in obese youth. The aim of the present study was to investigate the influence of OSA on cardiovascular functional parameters in obese youth. This is a prospective single-center observational cross-sectional study. Forty-four obese patients and 44 age- and gender-matched control subjects were included. All patients underwent polysomnography and cardiovascular assessment including functional echocardiography and carotid-femoral pulse wave velocity (PWV). Obese patients had higher left ventricular (LV) mass/height2.7, preserved LV systolic parameters, differences in LV diastolic parameters, and increased PWV and systolic blood pressure at rest compared with control group. In obese youth, 14 of 44 (32%) had OSA. There was no correlation between obesity and the apnea-hypopnea index (AHI). LV mass/height2.7 significantly correlated with body mass index z-score (r = 0.648, p <0.001) whereas PWV correlated with AHI (r = 0.352, p = 0.038). In obese patients, body mass index z-score was an independent predictor for LV mass/height2.7 (r = 0.61, p <0.001) and AHI was an independent predictor for higher PWV (r = 0.352, p = 0.038). In conclusion, both obesity and OSA influence cardiovascular performance in obese youth. Although obesity is associated with increased LV mass and reduced LV diastolic function, OSA is associated with changes in arterial stiffness.