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We present the case of a woman born with transposition of the great arteries, who was surgically repaired with the Mustard technique. Because of interatrial shunting, she was brought to the cardiac catheterization laboratory for device closure. Matrix-array 3D transesophageal echocardiography enabled visualization of both baffle leaks and demonstrated its orientation in a fashion superior to 2D imaging, had it been used alone. The leaks were successfully closed with a single transcatheter device. [ABSTRACT FROM AUTHOR]

No method of evaluating transthoracic echocardiograms (TTE) image quality (IQ) has been validated. Furthermore, structural echo lab elements impacting IQ are unknown. We sought to develop and validate a TTE IQ grading tool and determine patient and echo lab features associated with IQ. Ten pediatric echo labs each submitted 50 consecutive new patient TTEs without complex heart disease. For each study, 3 sonographers independently rated IQ and performed routine measurements. IQ scoring used the American College of Cardiology Quality Network (ACC QNet) tool plus a novel Likert scale component. IQ scores were validated against the ability to make measurements and, when all measurements were made, variation between sonographers. After validation, patient and lab factors, from a previously published survey, associated with improved TTE IQ were determined by linear regression. Total IQ score (R 2  = 0.64), ACC QNet (R 2  = 0.29) and the Likert component (R 2  = 0.52) correlated with the total number of measurements made (p < 0.001). For the 236 (52%) TTEs with all measurements, the Likert scale component (OR 0.9, 95% CI 0.82-0.99, p = 0.037) was associated with lower measurement variability. Factors significantly associated with worse IQ scores were higher patient weight, performance by a traveling sonographer, lower annual and inpatient TTE volume, less dedicated teaching/administrative sonographer time, and full-day sessions for reading physicians. A novel TTE IQ scoring tool was created and validated for pediatric TTE. Modifiable structural components of echo labs associated with TTE IQ were identified. This novel IQ tool should guide IQ beyond the ACC QNet score., Competing Interests: Declarations. Conflict of interest: Garick Hill served as a consultant for Ultragenyx. Ethical Approval: Not applicable. Consent to Participate: Not applicable., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: Cardiomyopathy is the leading cause of death in boys with Duchenne muscular dystrophy (DMD). While cardiac magnetic resonance (CMR) is routinely used to assess fibrosis and left ventricular (LV) ejection fraction, CMR measures of LV filling and ejection in DMD have not been reported., Methods: Patients with DMD (n=179) and healthy controls (n=96) were prospectively enrolled and underwent CMR. The DMD cohort was followed clinically at multiple institutions, and clinical data were recorded. Standard volumes and functions were calculated, and LV filling and ejection curves were measured from baseline CMR. Multivariable linear regressions were used to compare ventricular filling and ejection measures between groups, adjusting for baseline differences. Cox regressions were used to evaluate the relationship between diastolic function measures and mortality in the DMD cohort., Results: Patients with DMD had significantly smaller stature and ventricular volumes than healthy control patients ( P <0.001). They had lower baseline LV ejection fraction ( P <0.001), though most had normal systolic function. When adjusted for age, sex, heart rate, body surface area, and LV end-diastolic volume, patients with DMD had slower peak filling rates ( P <0.001) and peak ejection rates ( P <0.001), as well as slower time to peak ventricular ejection rate ( P =0.011). When adjusted for heart rate, a lower peak ventricular ejection rate ( P =0.007) and peak filling rate ( P =0.033), normalized to LV end-diastolic volume, were associated with mortality in patients with DMD., Conclusions: Patients with DMD have significantly different baseline CMR filling and ejection indices compared with controls. Some filling indices are associated with mortality and may be useful prognostic measures. Further research is needed in larger cohorts to determine the prognostic value of these differences., Competing Interests: None.

Background: Longitudinal evaluation of allograft diastolic function in paediatric heart transplant recipients is important for early detection of acute rejection, cardiac allograft vasculopathy, and graft dysfunction. Mean diastolic right atrial and pulmonary capillary wedge pressures obtained at catheterisation are the reference standards for assessment. Echocardiography is non-invasive and more suitable for serial surveillance, but individual parameters have lacked accuracy. This study aimed to identify covariates of post-transplant mean right atrial and pulmonary capillary wedge pressures, including B-type natriuretic peptide and certain echocardiographic parameters., Methods: A retrospective review of 143 scheduled cardiac catheterisations and echocardiograms from 56 paediatric recipients transplanted from 2007 to 2011 was performed. Samples with rejection were excluded. Univariate and multivariate linear regression models using backward selection were applied to a database consisting of B-type natriuretic peptide, haemodynamic, and echocardiographic data., Results: Ln B-type natriuretic peptide, heart rate z-score, left ventricular end-diastolic dimension z-score, mitral E/e', and percent interventricular septal thickening in systole were independently associated with mean right atrial pressure. Ln B-type natriuretic peptide, heart rate z-score, left ventricular end-diastolic dimension z-score, left ventricular mass (observed/predicted), and mitral E/e' were independently associated with mean pulmonary capillary wedge pressure. Covariates of B-type natriuretic peptide included mean pulmonary artery and pulmonary capillary wedge pressures, height, haemoglobin, fractional shortening, percent interventricular septal thickening in systole, and pulmonary vascular resistance index., Conclusions: B-type natriuretic peptide and echocardiographic indices of diastolic function were independently related to post-transplant mean right atrial and pulmonary capillary wedge pressures in paediatric heart transplant recipients without rejection.

Background: There are few data on practice patterns and trends for cardiovascular magnetic resonance (CMR) in pediatric and congenital heart disease. The Society for Cardiovascular Magnetic Resonance (SCMR) sought to address this deficiency by performing an international survey of CMR centers., Methods: Surveys consisting of 31 (2014) and 33 (2018) items were designed to collect data on the use of CMR for the evaluation of pediatric and congenital heart disease patients. They were sent to all SCMR members in 2014 and 2018. One response per center was collected., Results: There were 93 centers that responded in 2014 and 83 in 2018. The results that follow show data from 2014 and 2018 separated by a dash. The median annual number of pediatric/congenital CMR cases per center was 183-209. The median number of scanners for CMR was 2-2 (range, 1-8) with 58-63% using only 1.5T scanners and 4-4% using only 3T scanners. The mean number of attending/staff reading CMRs was 3.7-2.6; among them, 52-61% were pediatric or adult cardiologists and 47-38% were pediatric or adult radiologists. The median annual case volume per attending was 54-86. The median number of technologists per center doing CMRs was 4-5. The median scanner time allocated for a non-sedated examination was 75-75 min (range, 45-120). Among the 21 centers responding to both surveys, the mean annual case volume increased from 320 in 2014 to 445 in 2018; 17 (81%) of the centers had an increase in annual case volume. For this subgroup, the median attending/staff per center was 4 in both 2014 and 2018. The median scanner time allotted per study was unchanged at 90 min. The mean time for an attending/staff physician to perform a typical CMR examination including reporting was 143-141 min., Conclusion: These survey data provide a novel comprehensive view of CMR practice in pediatric and congenital heart disease. This information is useful for internal benchmarking, resource allocation, addressing practice variation, quality improvement initiatives, and identifying unmet needs., (© 2021. The Author(s).)

Background: Ventriculo-ventricular interactions are known to exist, though not well quantified. We hypothesised that the ventricular-vascular coupling ratio assessed by cardiovascular MRI would provide insight into this relationship. We also sought to compare MRI-derived ventricular-vascular coupling ratio to echocardiography and patient outcomes., Methods: Children with cardiac disease and biventricular physiology were included. Sanz's and Bullet methods were used to calculate ventricular-vascular coupling ratio by MRI and echocardiography, respectively. Subgroup analysis was performed for right and left heart diseases. Univariate and multivariate regressions were performed to determine associations with outcomes., Results: A total of 55 patients (age 14.3 ± 2.5 years) were included. Biventricular ventricular-vascular coupling ratio by MRI correlated with each other (r = 0.41; p = 0.003), with respect to ventricle's ejection fraction (r = -0.76 to -0.88; p < 0.001) and other ventricle's ejection fraction (r = -0.42 to -0.47; p < 0.01). However, biventricular ejection fraction had only weak correlation with each other (r = 0.31; p = 0.02). Echo underestimated ventricular-vascular coupling ratio for the left ventricle (p < 0.001) with modest correlation to MRI-derived ventricular-vascular coupling ratio (r = 0.43; p = 0.002). There seems to be a weak correlation between uncoupled right ventricular-vascular coupling ratio with the need for intervention and performance on exercise testing (r = 0.33; p = 0.02)., Conclusion: MRI-derived biventricular ventricular-vascular coupling ratio provides a better estimate of ventriculo-ventricular interaction in children and adolescents with CHD. These associations are stronger than traditional parameters and applicable to right and left heart conditions.

Introduction: Understanding congenital heart disease (CHD) is vital for medical personnel and parents of affected children. While traditional 2D schematics serve as the typical approach used, several studies have shown these models to be limiting in understanding complex structures. Recent world-emphasis has shifted to 3D printed models as a complement to 2D imaging to bridge knowledge and create new opportunities for experiential learning. We sought to systematically compare 3D digital and physical models for medical personnel and parent education compared to traditional methods., Methods: 3D printed and digital models were made out of MRI and CT data for 20 common CHD. Fellows and nurse practitioners used these models to explore intra-cardiac pathologies following traditional teaching. The models were also used for parent education in outpatient settings after traditional education. The participants were then asked to fill out a Likert scale questionnaire to assess their understanding and satisfaction with different teaching techniques. These ratings were compared using paired t-tests and Pearson's correlation., Results: Twenty-five medical personnel (18 fellows; 2 nurses; 4 nurse practitioners and one attending) and twenty parents participated in the study. The diagnosis varied from simple mitral valve pathology to complex single ventricle palliation. Parent and medical personnel perceived understanding with digital models was significantly higher than traditional (p = 0.01). Subjects also felt that physical models were overall more useful than digital ones (p = 0.001). Physicians using models for parent education also perceived the models to be useful, not significantly impacting their clinical workflow., Conclusions: 3D models, both digital and printed, enhance medical personnel and parental perceived understanding of CHD., (© 2021. The Author(s).)

Introduction: Appropriate use criteria (AUC) guide initial transthoracic echocardiogram (TTE) use in outpatient pediatrics. We sought to improve pediatric cardiologist TTE ordering appropriateness (mean AUC score) with a quality improvement initiative., Methods: The outcome of interest was the prospective AUC score for all initial outpatient TTEs ordered between November 2016 and August 2017, categorized per the AUC: "appropriate" (score 7-9), "may be appropriate" (4-6), "rarely appropriate" (1-3). Interventions included a didactic review of 2014 AUC and participant documentation of AUC criteria for each TTE. Participants met quarterly to evaluate outcome, process, and balancing measures, intervention effectiveness, and to identify and mitigate barriers., Results: Twenty-two pediatric cardiologists participated. TTE appropriateness level before (n = 216) and after (n = 557) intervention was high. There was no significant difference in mean baseline and post-intervention AUC score (7.42 ± 1.87 versus 7.16 ± 2.87, P = 0.1), nor in TTE sensitivity (27% versus 25%, P > 0.1) as a balancing measure. Among baseline studies, 81% were "appropriate," and 6% "rarely appropriate." Among post-intervention studies, 76% were "appropriate," and 11% "rarely appropriate." Barriers identified to implementing AUC include TTE indications not specified by current AUC, expectations of referring provider or parent to perform TTE, consistent provider application of AUC, and ability of AUC to capture comprehensive clinical judgment., Conclusions: Although the mean AUC appropriateness level was high, we were able to identify significant barriers to the implementation of AUC. Future efforts should focus on the reduction of "rarely appropriate" TTE ordering., Competing Interests: The authors have no financial interest to declare in relation to the content of this article., (Copyright © 2020 the Author(s). Published by Wolters Kluwer Health, Inc.)

Background: Longitudinal clinical surveillance by transthoracic echocardiography (TTE) is an established practice in children with repaired tetralogy of Fallot (TOF). Non-Invasive Imaging Guidelines recommends a list of reporting elements that should be addressed during routine TTE in this population. In this study, we assessed the adherence to these recommendations., Methods: This was a multi-center (n = 8) retrospective review of TTE reports in children ≤11 years of age who have had complete TOF repair. We included 10 patients from each participating center (n = 80) and scored 2 outpatient follow-up TTE reports on each patient. The adherence rate was based on completeness of TTE reporting elements derived from the guidelines., Results: We reviewed 160 TTE reports on 80 patients. Median age was 4.4 months (IQR 1.5-6.6) and 3.6 years (IQR 1.3-6.4) at the time of complete surgical repair and first TTE report, respectively. The median adherence rate to recommended reporting elements was 61% (IQR 53-70). Of the 160 reports, 9 (7%) were ≥80% adherent and 40 (25%) were ≥70% adherent. Quantitative measurements of right ventricular outflow tract (RVOT), right ventricular (RV) size and function, and branch pulmonary arteries were least likely to be reported., Conclusions: Overall adherence to the most recent published imaging guidelines for surveillance of children with repaired TOF patients was suboptimal, especially for reporting of RVOT, RV size and function, and branch pulmonary arteries. Further studies are needed to explore the barriers to adherence to guidelines and most importantly, whether adherence is associated with clinical outcomes., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Background: The reliability of left ventricular (LV) systolic functional indices calculated from blinded echocardiographic measurements of LV size has not been tested in a large cohort of healthy children. The objective of this study was to estimate interobserver variability in standard measurements of LV size and systolic function in children with normal cardiac anatomy and qualitatively normal function., Methods: The Pediatric Heart Network Normal Echocardiogram Database collected normal echocardiograms from healthy children ≤18 years old distributed equally by age, gender, and race. A core lab used two-dimensional echocardiograms to measure LV dimensions from which a separate data coordinating center calculated LV volumes and systolic functional indices. To evaluate interobserver variability, two independent expert pediatric echocardiographic observers remeasured LV dimensions on a subset of studies, while blinded to calculated volumes and functional indices., Results: Of 3,215 subjects with measurable images, 552 (17%) had a calculated LV shortening fraction (SF) < 25% and/or LV ejection fraction (EF) < 50%; the subjects were significantly younger and smaller than those with normal values. When the core lab and independent observer measurements were compared, individual LV size parameter intraclass correlation coefficients were high (0.81-0.99), indicating high reproducibility. The intraclass correlation coefficients were lower for SF (0.24) and EF (0.56). Comparing reviewers, 40/56 (71%) of those with an abnormal SF and 36/104 (35%) of those with a normal SF based on core lab measurements were calculated as abnormal from at least one independent observer. In contrast, an abnormal EF was less commonly calculated from the independent observers' repeat measures; only 9/47 (19%) of those with an abnormal EF and 8/113 (7%) of those with a normal EF based on core lab measurements were calculated as abnormal by at least one independent observer., Conclusions: Although blinded measurements of LV size show good reproducibility in healthy children, subsequently calculated LV functional indices reveal significant variability despite qualitatively normal systolic function. This suggests that, in clinical practice, abnormal SF/EF values may result in repeat measures of LV size to match the subjective assessment of function. Abnormal LV functional indices were more prevalent in younger, smaller children., (Copyright © 2019 American Society of Echocardiography. Published by Elsevier Inc. All rights reserved.)

We present an unusual case of concordant ventriculoarterial connections, subpulmonary infundibulum, and parallel arterial trunks. This case was complicated by extreme pulmonary artery tortuosity and low arching aorta causing severe tracheal compression. We discuss the difficulty in prenatal diagnosis, necessity for advanced imaging postnatally, and associated airway complications.

Objectives: Patients with Kawasaki disease can develop life-altering coronary arterial abnormalities, particularly in those resistant to intravenous immunoglobulin (IVIg) therapy. We tested the tumor necrosis factor α receptor antagonist etanercept for reducing both IVIg resistance and coronary artery (CA) disease progression., Methods: In a double-blind multicenter trial, patients with Kawasaki disease received either etanercept (0.8 mg/kg; n = 100) or placebo ( n = 101) subcutaneously starting immediately after IVIg infusion. IVIg resistance was the primary outcome with prespecified subgroup analyses according to age, sex, and race. Secondary outcomes included echocardiographic CA measures within subgroups defined by coronary dilation ( z score >2.5) at baseline. We used generalized estimating equations to analyze z score change and a prespecified algorithm for change in absolute diameters., Results: IVIg resistance occurred in 22% (placebo) and 13% (etanercept) of patients ( P = .10). Etanercept reduced IVIg resistance in patients >1 year of age ( P = .03). In the entire population, 46 (23%) had a coronary z score >2.5 at baseline. Etanercept reduced coronary z score change in those with and without baseline dilation ( P = .04 and P = .001); no improvement occurred in the analogous placebo groups. Etanercept ( n = 22) reduced dilation progression compared with placebo ( n = 24) by algorithm in those with baseline dilation ( P = .03). No difference in the safety profile occurred between etanercept and placebo., Conclusions: Etanercept showed no significant benefit in IVIg resistance in the entire population. However, preplanned analyses showed benefit in patients >1 year. Importantly, etanercept appeared to ameliorate CA dilation, particularly in patients with baseline abnormalities., Competing Interests: POTENTIAL CONFLICT OF INTEREST: The authors have indicated they have no potential conflicts of interest to disclose., (Copyright © 2019 by the American Academy of Pediatrics.)

Objectives: To report the results of the Nit-Occlud PDA prospective postapproval study (PAS) along with a comparison to the results of the pivotal and continued access trials., Background: The Nit-Occlud PDA (PFM Medical, Cologne, Germany), a nitinol coil patent ductus arteriosus (PDA) occluder, was approved by the Food and Drug Administration in 2013., Methods: The PAS enrolled a total of 184 subjects greater than 6 months of age, weighing at least 5 kg, with PDAs less than 4 mm by angiography at 11 centers. Patients were followed prospectively at 2 months, 12 months, and 24 months postprocedure. These outcomes were compared to the 357 subjects enrolled in the pivotal and continued access protocols. Efficacy and safety data were reported., Results: Among 184 subjects enrolled for the PAS between 2014 and 2017, 180 (97.8%) had successful device implantation. After 12 months, 98.7% (150/152) had trivial or no residual shunt by echocardiography and two subjects had only small residual shunts. There were three device embolizations that were all retrieved by snare without clinical consequence. Together with the pivotal and continued access study, 97.4% (449/461) had complete echocardiographic closure at 12 months in 541 enrolled subjects. The composite success was 94.4%. There were no mortalities and no serious device-related adverse events., Conclusions: The Nit-Occlud PDA is a safe and effective device for closure of a small to moderate sized PDA. There were no serious device-related adverse events in a large cohort of three clinical trials., (© 2018 The Authors. Catheterization and Cardiovascular Interventions published by Wiley Periodicals, Inc.)

Protein-based biotherapeutics are produced in engineered cells through complex processes and may contain a wide variety of variants and post-translational modifications that must be monitored or controlled to ensure product quality. Recently, a low level (~1-5%) impurity was observed in a number of proteins derived from stably transfected Chinese hamster ovary (CHO) cells using mass spectrometry. These molecules include antibodies and Fc fusion proteins where Fc is on the C-terminus of the construct. By liquid chromatography-mass spectrometry (LC-MS), the impurity was found to be ~1177 Da larger than the expected mass. After tryptic digestion and analysis by LC-MS/MS, the impurity was localized to the C-terminus of Fc in the form of an Fc sequence extension. Targeted higher-energy collision dissociation was performed using various normalized collision energies (NCE) on two charge states of the extended peptide, resulting in nearly complete fragment ion coverage. The amino acid sequence, SLSLSPEAEAASASELFQ, obtained by the de novo sequencing effort matches a portion of the vector sequence used in the transfection of the CHO cells, specifically in the promoter region of the selection cassette downstream of the protein coding sequence. The modification was the result of an unexpected splicing event, caused by the resemblance of the commonly used GGU codon of the C-terminal glycine to a consensus splicing donor. Three alternative codons for glycine were tested to alleviate the modification, and all were found to completely eliminate the undesirable C-terminal extension, thus improving product quality.

Background: The American Society of Echocardiography Committee on Pediatric Echocardiography Laboratory Productivity was formed in 2011 to study institutional factors that could influence the clinical productivity of physicians and sonographers in academic pediatric echocardiography laboratories. In the previous two surveys, staff clinical productivity remained stable while total echocardiography volumes increased. This third survey was designed to assess how clinical productivity is associated with laboratory infrastructure elements such as training, administrative tasks, quality improvement, research, and use of focused cardiac ultrasound (FCU)., Methods: Survey questions were sent by e-mail to North American laboratories. The aims were to assess (1) educational and training obligations, (2) academic productivity and research, (3) laboratory medical director satisfaction, (4) quality improvement, (5) laboratory leadership roles, and (6) impact and use of FCU. Survey responses were compared with clinical productivity metrics defined in the first two surveys., Results: There were 38 responses. Academic productivity was higher at institutions with more dedicated imaging personnel, personnel with dedicated protected academic time, and advanced imaging fellows. Academic productivity did not correlate with clinical productivity and was not significantly affected by the presence of dedicated research sonographers. The satisfaction level of laboratory medical directors was related to dedicated administrative time and an administrative stipend. The majority of administrative roles were tasked to the laboratory medical director with support of the technical director. FCU was listed as a hospital privilege at four institutions (13%). Twenty-two (58%) were training FCU providers in one or more subspecialties. FCU was not associated with clinical or academic productivity., Conclusions: This third survey gathered supplemental data to complement the clinical productivity data collected from the first two surveys. Together, the results of these surveys further describe the range of factors that can affect North American academic pediatric echocardiography laboratories., (Copyright © 2018 American Society of Echocardiography. Published by Elsevier Inc. All rights reserved.)

Background: The diagnosis of myocarditis presenting as isolated acute chest pain with elevated troponins but normal systolic function is challenging with significant drawbacks even for the gold-standard endomyocardial biopsy., Objective: This study aimed to evaluate the diagnostic role of strain imaging by echocardiography and cardiac MRI in these patients., Materials and Methods: This was a retrospective review of children with cardiac MRI for acute chest pain with elevated troponins compared to normal controls. Echocardiographic fractional shortening, ejection fraction, speckle-tracking-derived peak longitudinal, radial, and circumferential strain were compared to cardiac MRI ejection fraction, T2 imaging, late gadolinium enhancement, speckle-tracking-derived peak longitudinal strain, radial strain, and circumferential strain., Results: Group 1 included 10 subjects diagnosed with myocarditis, 9 (90%) males with a median age of 15.5 years (range: 14-17 years) compared with 10 age-matched controls in group 2. All subjects in group 1 had late gadolinium enhancement consistent with myocarditis and troponin ranged from 2.5 to >30 ng/ml. Electrocardiogram changes included ST segment elevation in 6 and abnormal Q waves in 1. Qualitative echocardiographic function was normal in both groups and mean fractional shortening was similar (35±6% in group 1 vs. 34±4% in group 2, P=0.70). Left ventricle ejection fraction by cardiac MRI, however, was lower in group 1 (52±9%) compared to group 2 at (59±4%) (P=0.03). Cardiac MRI derived strain was lower in group 1 vs. group 2 for speckle-tracking-derived peak longitudinal strain (-12.8±2.8% vs. -17.1±1.5%, P=0.001), circumferential strain (-12.3±3.8% vs. -15.8±1.2%, P=0.020) and radial strain (13.6±3.7% vs. 17.2±3.2%, P=0.040). Echocardiography derived strain was also lower in group 1 vs. group 2 for speckle-tracking-derived peak longitudinal strain (-15.6±3.9% vs. -20.8±2.2%, P<0.002), circumferential strain (-16±3% vs. -19.8±1.9%, P<0.003) and radial strain (17.3±6.1% vs. 24.8±6.3%, P=0.010)., Conclusion: In previously asymptomatic children, myocarditis can present with symptoms of acute chest pain suspicious for coronary ischemia. Cardiac MRI and echocardiographic strain imaging are noninvasive, radiation-free tests of immense diagnostic utility in these situations. Long-term studies are needed to assess prognostic significance of these findings.

Background: In CHD, three-dimensional strain analysis may overcome limitations of Doppler and two-dimensional strain of the left ventricle. The aims of this study were to evaluate feasibility and reproducibility of three-dimensional longitudinal, circumferential, and radial systolic strain by three-dimensional speckle-tracking echocardiography compared with two-dimensional echocardiography., Methods: Patients with CHD, biventricular circulation with a systemic left ventricle, and who had two- and three-dimensional imaging performed on the same day from 2010 to 2014 were included. Quantitative two- and three-dimensional strain analyses were performed (two-dimensional cardiac performance analysis version 1.2 and four-dimensional left ventricular analysis version 3.1). Intra- and inter-observer variabilities were calculated on 25 studies., Results: A total of 30 patients, including 19 (61%) males, with a median age of 3.6 years (0.1-22 years) were included. The mean fractional shortening was 34.6±5.3%, and the mean ejection fraction was 62.0±6.4%. Measurement of two- and three-dimensional strain was feasible in >95% of segments. Good correlation was observed between longitudinal and circumferential strain (r=0.92, p⩽0.001 and r=0.87, p⩽0.001), but not radial strain (r=0.29, p=0.2). Intra- and inter-observer agreements were better for three-dimensional compared with two-dimensional strain, and better for both two- and three-dimensional longitudinal and circumferential strains compared with radial strain., Conclusion: Left ventricular three-dimensional strain analysis is feasible in children with CHD. The reproducibility of longitudinal and circumferential strain by three-dimensional analyses is better. Further longitudinal studies are warranted for the potential clinical application of this new technology.

The voltage-gated sodium channel Na V 1.7 is a genetically validated pain target under investigation for the development of analgesics. A therapeutic with a less frequent dosing regimen would be of value for treating chronic pain; however functional Na V 1.7 targeting antibodies are not known. In this report, we describe Na V 1.7 inhibitory peptide-antibody conjugates as an alternate construct for potential prolonged channel blockade through chemical derivatization of engineered antibodies. We previously identified Na V 1.7 inhibitory peptide GpTx-1 from tarantula venom and optimized its potency and selectivity. Tethering GpTx-1 peptides to antibodies bifunctionally couples FcRn-based antibody recycling attributes to the Na V 1.7 targeting function of the peptide warhead. Herein, we conjugated a GpTx-1 peptide to specific engineered cysteines in a carrier anti-2,4-dinitrophenol monoclonal antibody using polyethylene glycol linkers. The reactivity of 13 potential cysteine conjugation sites in the antibody scaffold was tuned using a model alkylating agent. Subsequent reactions with the peptide identified cysteine locations with the highest conversion to desired conjugates, which blocked Na V 1.7 currents in whole cell electrophysiology. Variations in attachment site, linker, and peptide loading established design parameters for potency optimization. Antibody conjugation led to in vivo half-life extension by 130-fold relative to a nonconjugated GpTx-1 peptide and differential biodistribution to nerve fibers in wild-type but not Na V 1.7 knockout mice. This study describes the optimization and application of antibody derivatization technology to functionally inhibit Na V 1.7 in engineered and neuronal cells.

Background: The American Society of Echocardiography Committee on Pediatric Echocardiography Laboratory Productivity aimed to study factors that could influence the clinical productivity of physicians and sonographers and assess longitudinal trends for the same. The first survey results indicated that productivity correlated with the total volume of echocardiograms., Methods: Survey questions were designed to assess productivity for (1) physician full-time equivalent (FTE) allocated to echocardiography reading (echocardiograms per physician FTE per day), (2) sonographer FTE (echocardiograms per sonographer FTE per year), and (3) machine utilization (echocardiograms per machine per year). Questions were also posed to assess work flow and workforce., Results: For fiscal year 2013 or academic year 2012-2013, the mean number of total echocardiograms-including outreach, transthoracic, fetal, and transesophageal echocardiograms-per physician FTE per day was 14.3 ± 5.9, the mean number of echocardiograms per sonographer FTE per year was 1,056 ± 441, and the mean number of echocardiograms per machine per year was 778 ± 303. Both physician and sonographer productivity was higher at high-volume surgical centers and with echocardiography slots scheduled concordantly with clinic visits. Having an advanced imaging fellow and outpatient sedation correlated negatively with clinical laboratory productivity. Machine utilization was greater in laboratories with higher sonographer and physician productivity and lower for machines obtained before 2009., Conclusion: Measures of pediatric echocardiography laboratory staff productivity and machine utilization were shown to correlate positively with surgical volume, total echocardiography volumes, and concordant echocardiography scheduling; the same measures correlated negatively with having an advanced imaging fellow and outpatient sedation. There has been no significant change in staff productivity noted over two Committee on Pediatric Echocardiography Laboratory Productivity survey cycles, suggesting that hiring practices have matched laboratory volume increases., (Copyright © 2016 American Society of Echocardiography. Published by Elsevier Inc. All rights reserved.)

Background: Echocardiogram has limitations in effectively assessing right ventricular (RV) function in children post tetralogy of Fallot (TOF) repair. We evaluated the utility of speckle tracking echocardiography (STE)-based RV global longitudinal strain (GLS) for the assessment of RV systolic function., Methods: All patients with repaired TOF who had both echocardiograms and cardiac MRI (CMR) within a 6-month interval were included. RV volumes and ejection fraction (EF) were obtained by CMRs. Traditional echocardiographic function parameters and RV GLS were compared to CMR-derived RV EF. Subjects were divided into two groups based on CMR RV EF (group I: RV EF ≥45%; and group II: RV EF <45%)., Results: A total of 57 subjects were included. Mean age was 13.0±3.6 years and 58% were males. Group I had 39 subjects and group II had 18. Only six of the 18 patients (33%) in group II were identified as having at least mild RV dysfunction by echocardiogram. The mean RV GLS was significantly abnormal in group II (-15.3±3.8%) compared to group I (-20.9±3.3%; P<.001). By ROC analysis, an RV GLS cutoff value of -18% had 78% sensitivity and 77% specificity in identifying RV EF <45% (area under curve .87, P<.001). Intra- and inter-observer reproducibility of RV GLS were good., Conclusion: RV GLS is a simple and effective tool for the assessment of RV systolic function in patients post TOF repair. This technique would help further refine patient selection for timing of CMR and management., (© 2016, Wiley Periodicals, Inc.)

Background: Cardiomyopathy in Duchenne muscular dystrophy (DMD) is associated with death in approximately 40% of patients. Echocardiography is routinely used to assess left ventricular (LV) function; however, it has limitations in these patients., Objective: We compared echocardiographic measures of cardiac function assessment to cardiac MRI., Materials and Methods: We included children and young adults with DMD who had MRI performed between January 2010 and July 2015. We measured echocardiographic and MRI parameters of function assessment, including strain. Presence of late gadolinium enhancement (LGE) was assessed by MRI. Subjects were divided into two groups based on MRI left ventricular ejection fraction (LVEF): group I, LVEF ≥55% and group II, LVEF <55%., Results: We included 41 studies in 33 subjects, with 25 in group I and 16 in group II. Mean age of subjects was 13.6 ± 2.8 years and mean duration between echocardiogram and MRI was 7.6 ± 4.1 months. Only 8 of 16 (50%) patients in group II had diminished function on echocardiogram. Echocardiographic images were suboptimal in 16 subjects (39%). Overall, echocardiographic parameters had weak correlation with MRI-derived ejection fraction percentage. MRI-derived myocardial strain assessment has better correlation with MRI ejection fraction as compared to echocardiography-derived strain parameters., Conclusion: Echocardiography-based ventricular functional assessment has weak correlation with MRI parameters in children and young adults with Duchenne muscular dystrophy. While this correlation improves in the subset of subjects with adequate echocardiographic image quality, it remains modest and potentially suboptimal for clinical management. Accordingly, we conclude that MRI should be performed routinely and early in children with DMD, not only for LGE imaging but also for functional assessment.

Inhibition of the Wnt antagonist sclerostin increases bone mass in patients with osteoporosis and in preclinical animal models. Here we show increased levels of the Wnt antagonist Dickkopf-1 (DKK-1) in animals treated with sclerostin antibody, suggesting a negative feedback mechanism that limits Wnt-driven bone formation. To test our hypothesis that co-inhibition of both factors further increases bone mass, we engineer a first-in-class bispecific antibody with single residue pair mutations in the Fab region to promote efficient and stable cognate light-heavy chain pairing. We demonstrate that dual inhibition of sclerostin and DKK-1 leads to synergistic bone formation in rodents and non-human primates. Furthermore, by targeting distinct facets of fracture healing, the bispecific antibody shows superior bone repair activity compared with monotherapies. This work supports the potential of this agent both for treatment and prevention of fractures and offers a promising therapeutic approach to reduce the burden of low bone mass disorders.

Right ventricular dilation is a common complication after tetralogy of Fallot (TOF) repair. Traditional echocardiographic assessments are imprecise due to the RV's location and complex geometry. We propose a novel echocardiographic measurement: RV apical flattening (RVAF) as a screening tool to help identify subjects with severe RV dilation. Patients with repaired TOF who had both echocardiograms and CMR's within 6-month interval at our institution were included in the study. The RVAF was measured in the four-chamber echocardiographic view as the minor length of RV cavity at the level of RV apical endocardium. Subjects were divided into two groups (group I: RVEDVi ≥ 150 ml/m(2) and group II; RVEDVi < 150 ml/m(2)). Echocardiogram and CMR data were compared between groups. A total of 75 subjects were included in the study. Mean age was 12.8 ± 3.6 years. Group I had 36 subjects, and group II had 39 subjects. The mean RVAF was significantly higher in group I (2.7 ± 0.5 cm) compared with group II (1.7 ± 0.4 cm; p < 0.001). There was significant correlation between RVAF and RVEDVi (r = 0.81; p < 0.001). By ROC analysis, an RVAF cutoff value of 2.0 cm had 94 % sensitivity and 77 % specificity in identifying severe RV dilation (area under the curve 0.95). RVAF is a simple and effective echocardiographic screening tool to help identify severe RV dilation. In conjunction with other 2D echocardiographic parameters, this technique would help further refine echocardiography-guided patient selection for timing of CMR and pulmonary valve replacement.

Stainless steel embolization coils (SSEC) have been used for over four decades for vascular occlusion. Recently, the safety of these coils in a magnetic resonance environment has been called into question, with important ramifications for thousands of patients with existing coils in place. We performed a retrospective chart review at five tertiary care pediatric centers evaluating all children and young adults with implanted SSEC who underwent magnetic resonance imaging (MRI). Data reviewed included demographics, coil implantation, MRI studies, and follow-up evaluations. Complications such as heating, discomfort, or device migration were specifically sought. Two hundred and ninety-seven patients with implanted SSEC underwent 539 MRI examinations. The median age at SSEC implantation was 2.3 years (1 week-23.2 years). The MRI studies were performed a median of 7.4 years (4 days-23.1 years) after implantation. No patients experienced any reported complications associated with their MRI examinations during the study or at median follow-up post-MRI of 4.8 years (1 day-23 years). In this large, retrospective review of patients with implanted SSEC undergoing MRI, there were no reported adverse events. These findings support the recent change by Cook Medical Inc. of their standard embolization coils from a designation of magnetic resonance unsafe to conditional.

Background: Cardiac magnetic resonance imaging has demonstrated that the aortic root may be dilated in a dimension that two-dimensional echocardiography (2DE) is not able to interrogate. In the standard parasternal long-axis view, only a portion of the aortic root in the anteroposterior (AP) dimension can be visualized, as opposed to three-dimensional (3D) echocardiography (3DE), which can capture the entire root in an infinite number of planes. The purposes of the present study were to compare measurements of dilated aortic roots between 3DE and 2DE and to evaluate interobserver variability on 3DE., Methods: Thirty-one patients (median age, 13 years) with aortic root dilation were identified. Two-dimensional echocardiographic images and full-volume electrocardiographically gated 3D echocardiographic (3DE) images were obtained. Two blinded observers measured six dimensions of the aortic root in the short-axis view: three in the AP dimension and three in the transverse dimensions. Two-dimensional echocardiographic measurements were made by a third blinded observer. The largest AP 3DE measurement was compared with two-dimensional echocardiographic measurements. Interobserver 3DE measurements were also compared., Results: The median aortic root Z score was +2.63. Maximum 3DE measurement in any plane of the root size was significantly greater than on 2DE (P < .0001). The largest AP dimension by 3DE was significantly greater than on 2DE (P = .001). There was no significant interobserver variability for the largest dimension or those in the AP dimension, but a difference was found in the transverse dimension (P = .02)., Conclusions: Three-dimensional echocardiography compares favorably with 2DE in the evaluation of aortic root dilation in patients with known histories of aortic root disease. Three-dimensional echocardiography found that the largest diameter measured was significantly larger than on 2DE. The interobserver variability of 3DE is low, particularly in the AP dimension and in identifying the largest diameter. Three-dimensional echocardiography can be a useful technique in the periodic surveillance of patients with aortic root dilation., (Copyright © 2012 American Society of Echocardiography. Published by Mosby, Inc. All rights reserved.)

Recombinant proteins expressed in Escherichia coli are often produced as unfolded, inactive forms accumulated in inclusion bodies. Redox-coupled thiols are typically employed in the refolding process in order to catalyze the formation of correct disulfide bonds at maximal folding efficiency. These thiols and the recombinant proteins can form mixed disulfide bonds to generate thiol-protein adducts. In this work, we apply a fluorescent-based assay for the quantification of cysteine and cysteamine adducts as observed in E. coli-derived proteins. The thiols are released by reduction of the adducted protein, collected and labeled with a fluorescent reagent, 6-aminoquinolyl-N-hydroxysuccinimidyl carbamate. The derivatized thiols are separated by reversed-phase HPLC and can be accurately quantified after method optimization. The estimated thiol content represents total amount of adducted forms present in the analyzed samples. The limit of quantification (LOQ) was established; specifically, the lowest amount of quantifiable cysteine adduction is 30 picograms and the lowest amount of quantifiable cysteamine adduction is 60 picograms. The assay is useful for quantification of adducts in final purified products as well as in-process samples from various purification steps. The assay indicates that the purification process accomplishes a decrease in cysteine adduction from 0.19 nmol adduct/nmol protein to 0.03 nmol adduct/nmol protein as well as a decrease in cysteamine adduction from 0.24 nmol adduct/nmol protein to 0.14 nmol adduct/nmol protein., (Copyright © 2011. Published by Elsevier B.V.)

Background: quantitative assessment and validation of left ventricular (LV) volumes and mass in neonates and infants with complex congenital heart disease (CHD) is important for clinical management but has not been undertaken. We compared matrix-array 3D echocardiography (3D echo) measurements of volumes, mass, and ejection fraction (EF) with those measured by cardiac MRI in young patients with CHD and small LVs because of either young age or LV hypoplasia., Methods and Results: thirty-five patients aged <4 years (median, 0.8 years) undergoing MRI were prospectively enrolled. Three-dimensional echo was acquired immediately after MRI, and volume, mass, and EF measurements, using summation of discs methodology, were compared with MRI. Three-dimensional echo end-diastolic volume (24.4±15.7 versus 24.8±46.4 mL; P=0.01; intraclass correlation coefficient [ICC], 0.96) and end-systolic volume (12.3±8.6 versus 9.6±6.8 mL; P<0.001; ICC, 0.90) correlated with MRI with small mean differences (-0.49 mL [P=0.6] and 2.7 mL [P=0.001], respectively). Three-dimensional echo EF was smaller than MRI by 9.3% (P<0.001), and 3D echo LV mass measurements were comparable to MRI (17.3±10.3 versus 17.6±12 g; P<0.77; ICC, 0.93), with a small mean difference (1.1 g; P=0.28). There was good intra- and interobserver reliability for all measurements., Conclusions: in neonates and infants with CHD and small LVs (age appropriate or hypoplastic), matrix-array 3D echo measurements of mass and volumes compare well with MRI, providing an important modality for ventricular size and performance analysis in these patients, particularly in those with left-side heart obstructive lesions.