Design and implementation of multicenter pediatric and congenital studies with cardiovascular magnetic resonance: Big data in smaller bodies.

Cardiovascular magnetic resonance (CMR) has become the reference standard for quantitative and qualitative assessment of ventricular function, blood flow, and myocardial tissue characterization. There is a preponderance of large CMR studies and registries in adults; However, similarly powered studies are lacking for the pediatric and congenital heart disease (PCHD) population. To date, most CMR studies in children are limited to small single or multicenter studies, thereby limiting the conclusions that can be drawn. Within the PCHD CMR community, a collaborative effort has been successfully employed to recognize knowledge gaps with the aim to embolden the development and initiation of high-quality, large-scale multicenter research. In this publication, we highlight the underlying challenges and provide a practical guide toward the development of larger, multicenter initiatives focusing on PCHD populations, which can serve as a model for future multicenter efforts.

Augmented Biphasic Breathing Using Sniff and an Oral Positive Expiratory Pressure Device (Sniff-PEP) in Fontan Patients.

The use of an oral positive expiratory pressure device (oPEP) with sniff breathing (Sniff-PEP) mimics biphasic ventilation. Biphasic ventilation increases pulmonary blood flow and cardiac output in Fontan patients. The aim of this study was to assess the effect of Sniff-PEP on Fontan flow velocities. A single-center, pilot, prospective study was carried out in 15 subjects with Fontan circulation enrolled to use the oPEP device for 1 month. Subjects were instructed on Sniff-PEP and to use the device for 10-15 min 3-4 times a day. Measurements of flow velocity and cardiac output were measured via echocardiogram and quality of life assessments were performed at baseline and 4-6 weeks later. The mean age at enrollment was 19.9 ± 8.7 years (age range of 10-37 years). 7 patients (47%) had dominant left ventricle and 8 (53%) had an open fenestration. There was a statistically significant increase in flow velocities in the hepatic vein from 27.5 ± 7.6 to 35.1 ± 11.3 cm/s (p = 0.003), left pulmonary artery from 51.6 ± 16.6 to 57.6 ± 21.1 cm/s (p = 0.01), and right pulmonary artery from 43.1 ± 14.2 to 45.8 ± 17.2 cm/s (p = 0.04). With chronic use, the mean fenestration gradient slightly decreased from 4.5 ± 1.6 to 4.1 ± 1.9 mmHg but the difference was not statistically significant (p = 0.14). oPEP device therapy increased flow velocity in several areas in the Fontan circulation with acute use. Further studies are needed to assess the effects long term.Clinical Trial Registration: URL: https://clinicaltrials.gov . Unique identifier: NCT03251742.

Cardiac magnetic resonance haemodynamics in paediatric heart transplant patients: fick oximetry versus cardiac magnetic resonance phase contrast.

BACKGROUND: Lifetime radiation exposure for paediatric orthotopic heart transplant (OHT) patients is significant with cardiac catheterisation as the dominant source. Interventional cardiac magnetic resonance is utilised to obtain simultaneous, radiation-free haemodynamics and flow/function measurements. We sought to compare invasive haemodynamic measurements and radiation exposure in traditional cardiac catheterisation, to comprehensive interventional cardiac magnetic resonance. METHODS: Twenty-eight OHT patients who underwent 67 interventional cardiac magnetic resonance procedures at Children's National Hospital were identified. Both invasive oximetry with peripheral oxygen saturation (Fick) and cardiac magnetic resonance phase contrast measurements of pulmonary and systemic blood flow were performed. Systemic and pulmonary blood flow from the two modalities was compared using Bland-Altman, concordance analysis, and inter-reader correlation. A mixed model was implemented to account for confounding variables and repeat encounters. Radiation dosage data were collected for a contemporaneous cohort of orthotopic heart transplant patients undergoing standard, X-ray-guided catheterisation. RESULTS: Simultaneous cardiac magnetic resonance and Fick have poor agreement in our study based on Lin's correlation coefficient of 0.68 and 0.73 for pulmonary and systemic blood flow, respectively. Bland-Altman analysis demonstrated a consistent over estimation of cardiac magnetic resonance cardiac output by Fick. The average indexed dose area product for patients undergoing haemodynamics with endomyocardial biopsy was 0.73 (SD ±0.6) Gy*m2/kg. With coronary angiography added, the indexed dose area product was 14.6 (SD ± 7.8) Gy*m2/kg. CONCLUSIONS: Cardiac magnetic resonancemeasurements of cardiac output/index in paediatric orthotopic heart transplant patients have poor concordance with Fick estimates; however, cardiac magnetic resonance has good internal validity and inter-reader reliability. Radiation doses are small for haemodynamics with biopsy and increase exponentially with angiography, identifying a new target for cardiac magnetic resonance imaging.

A phantom for targeted endomyocardial biopsy training.

Endomyocardial biopsy (EMB) of the right ventricular (RV) septal surface during cardiac catheterization is the standard method to assess cardiac allograft rejection, heart failure, or inflammatory cardiomyopathies. We developed methodology using a three-dimensional (3D) printed phantom to provide proof of concept for using biplane overlay technology for targeted EMB. A standard bioptome and steerable sheath were used to discern feasibility of biopsy for seven regions of the RV septum guided by 3D overlay. This novel biopsy phantom can help train operators in biopsy techniques, and biplane overlay technology has the potential to advance targeted EMB in transplant and cardiomyopathy populations.

Multimodality Imaging in Ebstein Anomaly.

Ebstein anomaly is the most common form of tricuspid valve congenital anomalies. The tricuspid valve is abnormal with different degrees of displacement of the septal leaflet and abnormal rotation of the valve towards the right ventricular outflow tract. In severe forms, it results in significant tricuspid regurgitation and requires surgical repair. There is an increased interest in understanding the anatomy of the tricuspid valve in this lesion as the surgical repair has evolved with the invention and wide adoption of the cone operation. Multimodality imaging plays an important role in diagnosis, follow-up, surgical planning and post-operative care. This review provides anatomical tips for the cardiac imagers caring for patients with Ebstein anomaly and will help provide image-based personalized medicine.

Copper and Zinc Metal-Organic Frameworks with Bipyrazole Linkers Display Strong Antibacterial Activity against Both Gram+ and Gram- Bacterial Strains.

Here, we report a new synthetic protocol based on microwave-assisted synthesis (MAS) for the preparation of higher yields of zinc and copper in MOFs based on different bis(pyrazolyl)-tagged ligands ([M(BPZ)]n where M = Zn(II), Cu(II), H2BPZ = 4,4'-bipyrazole, [M(BPZ-NH2)]n where M = Zn(II), Cu(II); H2BPZ-NH2 = 3-amino-4,4'-bipyrazole, and [Mx(Me4BPZPh)] where M = Zn(II), x = 1; Cu(II), x = 2; H2Me4BPZPh = bis-4'-(3',5'-dimethyl)-pyrazolylbenzene) and, for the first time, a detailed study of their antibacterial activity, tested against Gram-negative (E. coli) and Gram-positive (S. aureus) bacteria, as representative agents of infections. The results show that all MOFs exert a broad-spectrum activity and strong efficiency in bacterial growth inhibition, with a mechanism of action based on the surface contact of MOF particles with bacterial cells through the so-called "chelation effect" and reactive oxygen species (ROS) generation, without a significant release of Zn(II) and Cu(II) ions. In addition, morphological changes were elucidated by using a scanning electron microscope (SEM) and bacterial cell damage was further confirmed by a confocal laser scanning microscopy (CLSM) test.

Statistical shape modeling reveals the link between right ventricular shape, hemodynamic force, and myocardial function in patients with repaired tetralogy of Fallot.

Patients with repaired tetralogy of Fallot (rTOF) can develop chronic pulmonary insufficiency (PI) with right ventricular (RV) dilation, progressive RV dysfunction, and decreased exercise capacity. Pulmonary valve replacement (PVR) can help reduce the amount of PI and RV dilation; however, optimal timing remains controversial; a better understanding of rTOF pathophysiology is of fundamental importance to inform clinical management of patients with rTOF and optimal timing of PVR. In this study, we hypothesize a tight interplay between RV shape, intracardiac biomechanics, and ventricular function in patients with rTOF. To explore this hypothesis and derive quantitative measures, we combined statistical shape modeling with physics-based analysis of in vivo 4D flow data in 36 patients with rTOF. Our study demonstrated for the first time a correlation between regional RV shape variations, hemodynamic forces (HDF), and clinical dysfunction in patients with rTOF. The main findings of this work include 1) general increase in RV size, due to both volume overload and physiological growth, correlated with decrease in strain magnitude in the respective directions, and with increased QRS; 2) regional PI-induced remodeling accounted for ∼10% of the shape variability of the population, and was associated with increased diastolic HDF along the diaphragm-to-right ventricular outflow tract (RVOT) direction, resulting in a net RV deformation along the same direction and decreased tricuspid annular plane systolic excursion (TAPSE); and 3) three shape modes independently correlated with systolic HDF and exercise capacity. Identification of patients based on the shape variations described in this study could help identify those at risk for irreversible dysfunction and guide optimal timing of PVR.NEW & NOTEWORTHY We combine statistical shape modeling with physics-based analysis of 4D flow data to elucidate the interplay between RV shape, hemodynamic forces, and clinical dysfunction in repaired tetralogy of Fallot. We are the first to show that ventricular remodeling is related to hemodynamic force magnitude and direction, global and regional functional parameters, and exercise intolerance. Identification of patients based on the shape variations described in this study could help identify those at risk for irreversible dysfunction.

Impact of ferumoxytol vs gadolinium on 4D flow cardiovascular magnetic resonance measurements in small children with congenital heart disease.

BACKGROUND: Cardiovascular magnetic resonance (CMR) allows for time-resolved three-dimensional phase-contrast (4D Flow) analysis of congenital heart disease (CHD). Higher spatial resolution in small infants requires thinner slices, which can degrade the signal. Particularly in infants, the choice of contrast agent (ferumoxytol vs. gadolinium) may influence 4D Flow CMR accuracy. Thus, we investigated the accuracy of 4D Flow CMR measurements compared to gold standard 2D flow phase contrast (PC) measurements in ferumoxytol vs. gadolinium-enhanced CMR of small CHD patients with shunt lesions. METHODS: This was a retrospective study consisting of CMR studies from complex CHD patients less than 20 kg who had ferumoxytol or gadolinium-enhanced 4D Flow and standard two-dimensional phase contrast (2D-PC) flow collected. 4D Flow clinical software (Arterys) was used to measure flow in great vessels, systemic veins, and pulmonary veins. 4D Flow accuracy was defined as percent difference or correlation against conventional measurements (2D-PC) from the same vessels. Subgroup analysis was performed on two-ventricular vs single-ventricular CHD, arterial vs venous flow, as well as low flows (defined as < 1.5 L/min) in 1V CHD. RESULTS: Twenty-one ferumoxytol-enhanced and 23 gadolinium-enhanced CMR studies were included, with no difference in age (2.1 ± 1.6 vs. 2.3 ± 1.9 years, p = 0.70), patient body surface area (0.50 ± 0.2 vs. 0.52 ± 0.2 m2, p = 0.67), or vessel diameter (11.4 ± 5.2 vs. 12.4 ± 5.6 mm, p = 0.22). Ten CMR studies with single ventricular CHD were included. Overall, ferumoxytol-enhanced 4D flow CMR measurements demonstrated less percent difference to 2D-PC when compared to gadolinium-enhanced 4D Flow CMR studies. In subgroup analyses of arterial vs. venous flows (high velocity vs. low velocity) and low flow in single ventricle CHD, ferumoxytol-enhanced 4D Flow CMR measurements had stronger correlation to 2D-PC CMR. The contrast-to-noise ratio (CNR) in ferumoxytol-enhanced studies was higher than the CNR in gadolinium-enhanced studies. CONCLUSIONS: Ferumoxytol-enhanced 4D Flow CMR has improved accuracy when compared to gadolinium 4D Flow CMR, particularly for infants with small vessels in CHD.

Native T1 mapping detects both acute clinical rejection and graft dysfunction in pediatric heart transplant patients.

BACKGROUND: Cardiovascular magnetic resonance (CMR) is emerging as an important tool for cardiac allograft assessment. Native T1 mapping may add value in identifying rejection and in assessing graft dysfunction and myocardial fibrosis burden. We hypothesized that CMR native T1 values and features of textural analysis of T1 maps would identify acute rejection, and in a secondary analysis, correlate with markers of graft dysfunction, and with fibrosis percentage from endomyocardial biopsy (EMB). METHODS: Fifty cases with simultaneous EMB, right heart catheterization, and 1.5 T CMR with breath-held T1 mapping via modified Look-Locker inversion recovery (MOLLI) in 8 short-axis slices and subsequent quantification of mean and peak native T1 values, were performed on 24 pediatric subjects. A single mid-ventricular slice was used for image texture analysis using nine gray-level co-occurrence matrix features. Digital quantification of Masson trichrome stained EMB samples established degree of fibrosis. Markers of graft dysfunction, including serum brain natriuretic peptide levels and hemodynamic measurements from echocardiography, catheterization, and CMR were collated. Subjects were divided into three groups based on degree of rejection: acute rejection requiring new therapy, mild rejection requiring increased ongoing therapy, and no rejection with no change in treatment. Statistical analysis included student's t-test and linear regression. RESULTS: Peak and mean T1 values were significantly associated with acute rejection, with a monotonic trend observed with increased grade of rejection. Texture analysis demonstrated greater spatial heterogeneity in T1 values, as demonstrated by energy, entropy, and variance, in cases requiring treatment. Interestingly, 2 subjects who required increased therapy despite low grade EMB results had abnormal peak T1 values. Peak T1 values also correlated with increased BNP, right-sided filling pressures, and capillary wedge pressures. There was no difference in histopathological fibrosis percentage among the 3 groups; histopathological fibrosis did not correlate with T1 values or markers of graft dysfunction. CONCLUSION: In pediatric heart transplant patients, native T1 values identify acute rejection requiring treatment and may identify graft dysfunction. CMR shows promise as an important tool for evaluation of cardiac grafts in children, with T1 imaging outperforming biopsy findings in the assessment of rejection.

Cardiac MRI-Derived Inferior Vena Cava Cross-Sectional Area Correlates with Measures of Fontan-Associated Liver Disease.

There is currently no clear consensus on screening techniques to evaluate the presence or severity of Fontan-associated liver disease (FALD). Cardiac MRI (CMR) is used routinely for post-Fontan surveillance, but CMR-derived measures that relate to the severity of FALD are not yet defined. This was a cross-sectional single-center study of post-Fontan patients who underwent a CMR. CMR exams were re-analyzed by a single pediatric cardiologist. Surrogates of FALD included Gamma-Glutamyl Transferase (GGT), Fibrosis-4 laboratory score (FIB-4), and imaging findings. Findings consistent with cirrhosis on liver ultrasound included increased liver echogenicity and/or nodularity. Statistical analyses were performed to investigate potential relationships between CMR parameters and markers of FALD. Sixty-one patients were included. A larger inferior vena cava cross-sectional area (IVC-CSA) indexed to height was significantly associated with a higher FIB-4 score (Spearman's ρ = 0.28, p = 0.04), a higher GGT level (Spearman's ρ = 0.40, p = 0.02), and findings consistent with cirrhosis on liver ultrasound (OR 1.17, 95% CI: (1.01, 1.35), p = 0.04). None of the other CMR parameters were associated with markers of FALD. A larger indexed IVC-CSA was associated with higher systemic ventricle end-diastolic pressure (EDP) on cardiac catheterization (Spearman's ρ = 0.39, p = 0.018) as well as older age (Spearman's ρ = 0.46, p = < 0.001). Indexed IVC-CSA was the only CMR parameter that was associated with markers of FALD. This measure has the potential to serve as an additional non-invasive tool to improve screening strategies for FALD. Visual abstract summarizing the primary findings of this paper.

Combining patient-specific, digital 3D models with tele-education for adolescents with CHD.

INTRODUCTION: Adolescents with CHD require transition to specialised adult-centred care. Previous studies have shown that adolescents' knowledge of their medical condition is correlated with transition readiness. Three-dimensional printed models of CHD have been used to educate medical trainees and patients, although no studies have focused on adolescents with CHD. This study investigates the feasibility of combining patient-specific, digital 3D heart models with tele-education interventions to improve the medical knowledge of adolescents with CHD. METHODS: Adolescent patients with CHD, aged between 13 and 18 years old, were enrolled and scheduled for a tele-education session. Patient-specific digital 3D heart models were created using images from clinically indicated cardiac magnetic resonance studies. The tele-education session was performed using commercially available, web-conferencing software (Zoom, Zoom Video Communications Inc.) and a customised software (Cardiac Review 3D, Indicated Inc.) incorporating an interactive display of the digital 3D heart model. Medical knowledge was assessed using pre- and post-session questionnaires that were scored by independent reviewers. RESULTS: Twenty-two adolescents completed the study. The average age of patients was 16 years old (standard deviation 1.5 years) and 56% of patients identified as female. Patients had a variety of cardiac defects, including tetralogy of Fallot, transposition of great arteries, and coarctation of aorta. Post-intervention, adolescents' medical knowledge of their cardiac defects and cardiac surgeries improved compared to pre-intervention (p < 0.01). CONCLUSIONS: Combining patient-specific, digital 3D heart models with tele-education sessions can improve adolescents' medical knowledge and may assist with transition to adult-centred care.

Cardiac echocardiogram findings of severe acute respiratory syndrome coronavirus-2-associated multi-system inflammatory syndrome in children.

BACKGROUND: A novel paediatric disease, multi-system inflammatory syndrome in children, has emerged during the 2019 coronavirus disease pandemic. OBJECTIVES: To describe the short-term evolution of cardiac complications and associated risk factors in patients with multi-system inflammatory syndrome in children. METHODS: Retrospective single-centre study of confirmed multi-system inflammatory syndrome in children treated from 29 March, 2020 to 1 September, 2020. Cardiac complications during the acute phase were defined as decreased systolic function, coronary artery abnormalities, pericardial effusion, or mitral and/or tricuspid valve regurgitation. Patients with or without cardiac complications were compared with chi-square, Fisher's exact, and Wilcoxon rank sum. RESULTS: Thirty-nine children with median (interquartile range) age 7.8 (3.6-12.7) years were included. Nineteen (49%) patients developed cardiac complications including systolic dysfunction (33%), valvular regurgitation (31%), coronary artery abnormalities (18%), and pericardial effusion (5%). At the time of the most recent follow-up, at a median (interquartile range) of 49 (26-61) days, cardiac complications resolved in 16/19 (84%) patients. Two patients had persistent mild systolic dysfunction and one patient had persistent coronary artery abnormality. Children with cardiac complications were more likely to have higher N-terminal B-type natriuretic peptide (p = 0.01), higher white blood cell count (p = 0.01), higher neutrophil count (p = 0.02), severe lymphopenia (p = 0.05), use of milrinone (p = 0.03), and intensive care requirement (p = 0.04). CONCLUSION: Patients with multi-system inflammatory syndrome in children had a high rate of cardiac complications in the acute phase, with associated inflammatory markers. Although cardiac complications resolved in 84% of patients, further long-term studies are needed to assess if the cardiac abnormalities (transient or persistent) are associated with major cardiac events.

Moving beyond size: vorticity and energy loss are correlated with right ventricular dysfunction and exercise intolerance in repaired Tetralogy of Fallot.

BACKGROUND: The global effect of chronic pulmonary regurgitation (PR) on right ventricular (RV) dilation and dysfunction in repaired Tetralogy of Fallot (rTOF) patients is well studied by cardiovascular magnetic resonance (CMR). However, the links between PR in the RV outflow tract (RVOT), RV dysfunction and exercise intolerance are not clarified by conventional measurements. Not all patients with RV dilation share the same intracardiac flow characteristics, now measurable by time resolved three-dimensional phase contrast imaging (4D flow). In our study, we quantified regional vorticity and energy loss in rTOF patients and correlated these parameters with RV dysfunction and exercise capacity. METHODS: rTOF patients with 4D flow datasets were retrospectively analyzed, including those with transannular/infundibular repair and conduit repair. Normal controls and RV dilation patients with atrial-level shunts (Qp:Qs > 1.2:1) were included for comparison. 4D flow was post-processed using IT Flow (Cardioflow, Japan). Systolic/diastolic vorticity (ω, 1/s) and viscous energy loss (VEL, mW) in the RVOT and RV inflow were measured. To characterize the relative influence of diastolic vorticity in the two regions, an RV Diastolic Vorticity Quotient (ωRVOT-Diastole/ωRV Inflow-Diastole, RV-DVQ) was calculated. Additionally, RVOT Vorticity Quotient (ωRVOT-Diastole/ωRVOT-Systole, RVOT-VQ) and RVOT Energy Quotient (VELRVOT-Diastole/VELRVOT-Systole, RVOT-EQ) was calculated. In rTOF, measurements were correlated against conventional CMR and exercise stress test results. RESULTS: 58 rTOF patients, 28 RV dilation patients and 12 controls were included. RV-DVQ, RVOT-VQ, and RVOT-EQ were highest in rTOF patients with severe PR compared to rTOF patients with non-severe PR, RV dilation and controls (p < 0.001). RV-DVQ positively correlated with RV end-diastolic volume (0.683, p < 0.001), PR fraction (0.774, p < 0.001) and negatively with RV ejection fraction (- 0.521, p = 0.003). Both RVOT-VQ, RVOT-EQ negatively correlated with VO2-max (- 0.587, p = 0.008 and - 0.617, p = 0.005) and % predicted VO2-max (- 0.678, p = 0.016 and - 0.690, p = 0.001). CONCLUSIONS: In rTOF patients, vorticity and energy loss dominate the RVOT compared to tricuspid inflow, correlating with RV dysfunction and exercise intolerance. These 4D flow-based measurements may be sensitive biomarkers to guide surgical management of rTOF patients.

Altered hemodynamics by 4D flow cardiovascular magnetic resonance predict exercise intolerance in repaired coarctation of the aorta: an in vitro study.

BACKGROUND: Coarctation of the aorta (CoA) is associated with decreased exercise capacity despite successful repair. Altered flow patterns have been identified due to abnormal aortic arch geometry. Our previous work demonstrated aorta size mismatch to be associated with exercise intolerance in this population. In this study, we studied aortic flow patterns during simulations of exercise in repaired CoA using 4D flow cardiovascular magnetic resonance (CMR) using aortic replicas connected to an in vitro flow pump and correlated findings with exercise stress test results to identify biomarkers of exercise intolerance. METHODS: Patients with CoA repair were retrospectively analyzed after CMR and exercise stress test. Each aorta was manually segmented and 3D printed. Pressure gradient measurements from ascending aorta (AAo) to descending aorta (DAo) and 4D flow CMR were performed during simulations of rest and exercise using a mock circulatory flow loop. Changes in wall shear stress (WSS) and secondary flow formation (vorticity and helicity) from rest to exercise were quantified, as well as estimated DAo Reynolds number. Parameters were correlated with percent predicted peak oxygen consumption (VO2max) and aorta size mismatch (DAAo/DDAo). RESULTS: Fifteen patients were identified (VO2max 47 to 126% predicted). Pressure gradient did not correlate with VO2max at rest or exercise. VO2max correlated positively with the change in peak vorticity (R = 0.55, p = 0.03), peak helicity (R = 0.54, p = 0.04), peak WSS in the AAo (R = 0.68, p = 0.005) and negatively with peak WSS in the DAo (R = - 0.57, p = 0.03) from rest to exercise. DAAo/DDAo correlated strongly with change in vorticity (R = - 0.38, p = 0.01), helicity (R = - 0.66, p = 0.007), and WSS in the AAo (R = - 0.73, p = 0.002) and DAo (R = 0.58, p = 0.02). Estimated DAo Reynolds number negatively correlated with VO2max for exercise (R = - 0.59, p = 0.02), but not rest (R = - 0.28, p = 0.31). Visualization of streamline patterns demonstrated more secondary flow formation in aortic arches with better exercise capacity, larger DAo, and lower Reynolds number. CONCLUSIONS: There are important associations between secondary flow characteristics and exercise capacity in repaired CoA that are not captured by traditional pressure gradient, likely due to increased turbulence and inefficient flow. These 4D flow CMR parameters are a target of investigation to identify optimal aortic arch geometry and improve long term clinical outcomes after CoA repair.

Society for Cardiovascular Magnetic Resonance 2020 Case of the Week series.

The Society for Cardiovascular Magnetic Resonance (SCMR) is an international society focused on the research, education, and clinical application of cardiovascular magnetic resonance (CMR). Case of the week is a case series hosted on the SCMR website ( https://www.scmr.org ) that demonstrates the utility and importance of CMR in the clinical diagnosis and management of cardiovascular disease. Each case consists of the clinical presentation and a discussion of the condition and the role of CMR in diagnosis and guiding clinical management. The cases are all instructive and helpful in the approach to patient management. We present a digital archive of the 2020 Case of the Week series of 11 cases as a means of further enhancing the education of those interested in CMR and as a means of more readily identifying these cases using a PubMed or similar search engine.

Impact of incorporating echocardiographic screening into a clinical prediction model to optimise utilisation of echocardiography in primary care.

INTRODUCTION: Access to public subspecialty healthcare is limited in underserved areas of Brazil, including echocardiography (echo). Long waiting lines and lack of a prioritisation system lead to diagnostic lag and may contribute to poor outcomes. We developed a prioritisation tool for use in primary care, aimed at improving resource utilisation, by predicting those at highest risk of having an abnormal echo, and thus in highest need of referral. METHODS: All patients in the existing primary care waiting list for echo were invited for participation and underwent a clinical questionnaire, simplified 7-view echo screening by non-physicians with handheld devices, and standard echo by experts. Two derivation models were developed, one including only clinical variables and a second including clinical variables and findings of major heart disease (HD) on echo screening (cut point for high/low-risk). For validation, patients were risk-classified according to the clinical score. High-risk patients and a sample of low-risk underwent standard echo. Intermediate-risk patients first had screening echo, with a standard echo if HD was suspected. Discrimination and calibration of the two models were assessed to predict HD in standard echo. RESULTS: In derivation (N = 603), clinical variables associated with HD were female gender, body mass index, Chagas disease, prior cardiac surgery, coronary disease, valve disease, hypertension and heart failure, and this model was well calibrated with C-statistic = 0.781. Performance was improved with the addition of echo screening, with C-statistic = 0.871 after cross-validation. For validation (N = 1526), 227 (14.9%) patients were classified as low risk, 1082 (70.9%) as intermediate risk and 217 (14.2%) as high risk by the clinical model. The final model with two categories had high sensitivity (99%) and negative predictive value (97%) for HD in standard echo. Model performance was good with C-statistic = 0.720. CONCLUSION: The addition of screening echo to clinical variables significantly improves the performance of a score to predict major HD.

Normal right and left ventricular volumes prospectively obtained from cardiovascular magnetic resonance in awake, healthy, 0- 12 year old children.

INTRODUCTION: Pediatric z scores are necessary to describe size and structure of the heart in growing children, however, development of an accurate z score calculator requires robust normal datasets, which are difficult to obtain with cardiovascular magnetic resonance (CMR) in children. Motion-corrected (MOCO) cines from re-binned, reconstructed real-time cine offer a free-breathing, rapid acquisition resulting in cines with high spatial and temporal resolution. In combination with child-friendly positioning and entertainment, MOCO cine technique allows for rapid cine volumetry in patients of all ages without sedation. Thus, our aim was to prospectively enroll normal infants and children birth-12 years for creation and validation of a z score calculator describing normal right ventricular (RV) and left ventricular (LV) size. METHODS: With IRB approval and consent/assent, 149 normal children successfully underwent a brief noncontrast CMR on a 1.5 T scanner including MOCO cines in the short axis, and RV and LV volumes were measured. 20% of scans were re-measured for interobserver variability analyses. A general linear modeling (GLM) framework was employed to identify and properly represent the relationship between CMR-based assessments and anthropometric data. Scatter plots of model fit and Akaike's information criteria (AIC) results were used to guide the choice among alternative models. RESULTS: A total of 149 subjects aged 22 days-12 years (average 5.1 ± 3.6 years), with body surface area (BSA) range 0.21-1.63 m2 (average 0.8 ± 0.35 m2) were scanned. All ICC values were > 95%, reflecting excellent agreement between raters. The model that provided the best fit of volume measure to the data included BSA with higher order effects and gender as independent variables. Compared with earlier z score models, there is important additional growth inflection in early toddlerhood with similar z score prediction in later childhood. CONCLUSIONS: Free-breathing, MOCO cines allow for accurate, reliable RV and LV volumetry in a wide range of infants and children while awake. Equations predicting fit between LV and RV normal values and BSA are reported herein for purposes of creating z scores. TRIAL REGISTRATION: clinicaltrials.gov NCT02892136, Registered 7/21/2016.

Motion-corrected cardiac MRI is associated with decreased anesthesia exposure in children.

BACKGROUND: The benefits of cardiac magnetic resonance imaging (MRI) in the pediatric population must be balanced with the risk and cost of anesthesia. Segmented imaging using multiple averages attempts to avoid breath-holds requiring general anesthesia; however, cardiorespiratory artifacts and prolonged scan times limit its use. Thus, breath-held imaging with general anesthesia is used in many pediatric centers. The advent of free-breathing, motion-corrected (MOCO) cines by real-time re-binned reconstruction offers reduced anesthesia exposure without compromising image quality. OBJECTIVE: This study evaluates sedation utilization in our pediatric cardiac MR practice before and after clinical introduction of free-breathing MOCO imaging for cine and late gadolinium enhancement. MATERIALS AND METHODS: In a retrospective study, patients referred for a clinical cardiac MR who would typically be offered sedation for their scan (n=295) were identified and divided into two eras, those scanned before the introduction of MOCO cine and late gadolinium enhancement sequences and those scanned following their introduction. Anesthesia use was compared across eras and disease-specific cohorts. RESULTS: The incidence of non-sedation studies performed in children nearly tripled following the introduction of MOCO imaging (25% [pre-MOCO] to 69% [post-MOCO], P<0.01), with the greatest effect in patients with simple congenital heart disease. Eleven percent of the post-MOCO cohort comprised infants younger than 3 months of age who could forgo sedation with the combination of MOCO imaging and a "feed-and-bundle" positioning technique. CONCLUSION: Implementation of cardiac MR with MOCO cine and late gadolinium enhancement imaging in a pediatric population is associated with significantly decreased sedation utilization.

Troponin I Levels Correlate with Cardiac MR LGE and Native T1 Values in Duchenne Muscular Dystrophy Cardiomyopathy and Identify Early Disease Progression.

Cardiomyopathy is the leading cause of death in Duchenne muscular dystrophy (DMD). Elevated troponin levels are observed in DMD and may vary with disease progression. We studied troponin levels in DMD related to cardiac fibrosis and native T1 measures. This is a prospective, cross-sectional, observational study of 30 DMD subjects measuring native T1 levels and late gadolinium enhancement (LGE) on cardiac MR imaging (CMR) correlated with temporally associated serum troponin I levels. Non-parametric analyses including Spearman correlations and Kruskal-Wallis test were performed between groups. p values resulting from the pair-wise comparisons were adjusted for multiple comparisons using the Sidak method where appropriate. There were 15 DMD subjects with no LGE (age 12 ± 3 yo; EF% 60 ± 5) and troponin I level of 0.05 ± 0.08 ng/ml, of which three had an abnormal troponin level (over 0.04 ng/ml); 7 DMD subjects with mild LGE (age 17 ± 5 yo, EF% 52 ± 8) and troponin I level of 0.28 ± 0.36 ng/ml, of which five had an abnormal troponin level; and 8 DMD subjects with moderate-to-severe LGE (age 16 ± 6 yo; EF% 54 ± 8) and troponin I level of 0.11 ± 0.14 ng/ml, of which four had an abnormal troponin level. Troponin I levels in DMD subjects with mild LGE was significantly increased compared to subjects with no LGE (p = 0.02). There was a statistically significant positive correlation between troponin I levels and MOLLI septal native T1 values (r2 = 0.173, p = 0.02). Overall, MOLLI lateral native T1 levels were increased with moderate-severe LGE compared to mild and none (p < 0.01). Serum biomarker troponin I levels were increased in DMD subjects with mild LGE and correlated with MOLLI septal native T1 values. Troponin I levels may be a useful minimally invasive outcome marker to monitor myocardial disease progression in DMD cardiomyopathy.

Quantitative cardiac magnetic resonance T2 imaging offers ability to non-invasively predict acute allograft rejection in children.

BACKGROUND: Monitoring for acute allograft rejection improves outcomes after cardiac transplantation. Endomyocardial biopsy is the gold standard test defining rejection, but carries risk and has limitations. Cardiac magnetic resonance T2 mapping may be able to predict rejection in adults, but has not been studied in children. Our aim was to evaluate T2 mapping in identifying paediatric cardiac transplant patients with acute rejection. METHODS: Eleven paediatric transplant patients presenting 18 times were prospectively enrolled for non-contrast cardiac magnetic resonance at 1.5 T followed by endomyocardial biopsy. Imaging included volumetry, flow, and T2 mapping. Regions of interest were manually selected on the T2 maps using the middle-third technique in the left ventricular septal and lateral wall in a short-axis and four-chamber slice. Mean and maximum T2 values were compared with Student's t-tests analysis. RESULTS: Five cases of acute rejection were identified in three patients, including two cases of grade 2R on biopsy and three cases of negative biopsy treated for clinical symptoms attributed to rejection (new arrhythmia, decreased exercise capacity). A monotonic trend between increasing T2 values and higher biopsy grades was observed: grade 0R T2 53.4 ± 3 ms, grade 1R T2 54.5 ms ± 3 ms, grade 2R T2 61.3 ± 1 ms. The five rejection cases had significantly higher mean T2 values compared to cases without rejection (58.3 ± 4 ms versus 53 ± 2 ms, p = 0.001). CONCLUSIONS: Cardiac magnetic resonance with quantitative T2 mapping may offer a non-invasive method for screening paediatric cardiac transplant patients for acute allograft rejection. More data are needed to understand the relationship between T2 and rejection in children.