Cardiac MRI evaluation of aortic biophysical properties in paediatric Turner syndrome.

BACKGROUND: Aortopathy in Turner syndrome is associated with aortic dilation, and the risk of dissection is increased when the aortic size index is ≥ 2-2.5 cm/m2. We evaluated the aortic biophysical properties in paediatric Turner syndrome using cardiac MRI to determine their relationship to aortic size index. METHODS: Turner syndrome patients underwent cardiac MRI to evaluate ventricular function, aortic dimensions, and biophysical properties (aortic stiffness index, compliance, distensibility, pulse wave velocity, and aortic and left ventricular elastance). Spearman correlation examined correlations between these properties and aortic size index. Data was compared to 10 controls. RESULTS: Of 25 Turner syndrome patients, median age 14.7 years (interquartile range: 11.0-16.8), height z score -2.7 (interquartile range: -2.92 - -1.54), 24% had a bicuspid aortic valve. Turner syndrome had increased diastolic blood pressure (p < 0.001) and decreased left ventricular end-diastolic (p < 0.001) and end-systolic (p = 0.002) volumes compared to controls. Median aortic size index was 1.81 cm/m2 (interquartile range: 1.45-2.1) and 7 had an aortic size index > 2 cm/m2. Aortic and left ventricular elastance were greater in Turner syndrome compared to controls (both p < 0.001). Increased aortic size index correlated with increased aortic elastance (r = 0.5, p = 0.01) and left ventricular elastance (r = 0.59, p = 0.002) but not aortic compliance. Higher ascending aortic areas were associated with increased aortic compliance (r = 0.44, p = 0.03) and left ventricular elastance (r = 0.49, p = 0.01). CONCLUSION: Paediatric Turner syndrome with similar aortic size index to controls showed MRI evidence of abnormal aortic biophysical properties. These findings point to an underlying aortopathy and provide additional parameters that may aid in determining risk factors for aortic dissection.

Natural History of Secundum ASD in Preterm and Term Neonates: A Comparative Study.

Atrial septal defects (ASDs) are common in neonates. Although past studies suggest ASDs  ≥ 3 mm in term neonates (TNs) are less likely to close, there is paucity of data regarding the natural history in preterm neonates (PNs), information that would inform surveillance. We sought to compare spontaneous closure rates and need for intervention for ASDs in TNs/near term (≥ 36 weeks) versus PNs (< 36 weeks). We included all TNs and PNs who underwent echocardiography at ≤ 1 month between 2010 and 2018 in our institution with an ASD ≥ 3 mm, without major congenital heart disease, and with repeat echocardiogram(s). Spontaneous resolution was defined as size diminution to < 3 mm or closure. We included 156 TNs (mean gestational age at birth 38.6 ± 1.4 weeks) and 156 PNs (29.6 ± 3.7 weeks) with a mean age at follow-up of 16 ± 19 and 15 ± 21 months, respectively (p = 0.76). Based on maximum color Doppler diameter, in TNs, ASD resolution occurred in 95% of small (3-5 mm), 87% of moderate (5.1-8 mm), and 60% of large (> 8 mm) defects; whereas, in PNs, resolution occurred in 79% of small, 76% of moderate, and 33% of large ASDs. There was a significant association between size and ASD resolution in TNs (p = 0.003), but not PNs (p = 0.17). Overall, ASD resolution rate was higher in TNs (89%) versus PNs (78%) (p = 0.009), and fewer TNs (1%) compared to PNs (7%) required ASD intervention (p = 0.02). Most ASDs identified in TNs and PNs spontaneously resolve. PNs, however, demonstrate lower ASD resolution and higher intervention rates within all size groups. These data should inform follow-up of affected neonates.

Obesity and Outcomes of Kawasaki Disease and COVID-19-Related Multisystem Inflammatory Syndrome in Children.

Importance: Obesity may affect the clinical course of Kawasaki disease (KD) in children and multisystem inflammatory syndrome in children (MIS-C) associated with COVID-19. Objective: To compare the prevalence of obesity and associations with clinical outcomes in patients with KD or MIS-C. Design, Setting, and Participants: In this cohort study, analysis of International Kawasaki Disease Registry (IKDR) data on contemporaneous patients was conducted between January 1, 2020, and July 31, 2022 (42 sites, 8 countries). Patients with MIS-C (defined by Centers for Disease Control and Prevention criteria) and patients with KD (defined by American Heart Association criteria) were included. Patients with KD who had evidence of a recent COVID-19 infection or missing or unknown COVID-19 status were excluded. Main Outcomes and Measures: Patient demographic characteristics, clinical features, disease course, and outcome variables were collected from the IKDR data set. Using body mass index (BMI)/weight z score percentile equivalents, patient weight was categorized as normal weight (BMI <85th percentile), overweight (BMI ≥85th to <95th percentile), and obese (BMI ≥95th percentile). The association between adiposity category and clinical features and outcomes was determined separately for KD and MIS-C patient groups. Results: Of 1767 children, 338 with KD (median age, 2.5 [IQR, 1.2-5.0] years; 60.4% male) and 1429 with MIS-C (median age, 8.7 [IQR, 5.3-12.4] years; 61.4% male) were contemporaneously included in the study. For patients with MIS-C vs KD, the prevalence of overweight (17.1% vs 11.5%) and obesity (23.7% vs 11.5%) was significantly higher (P < .001), with significantly higher adiposity z scores, even after adjustment for age, sex, and race and ethnicity. For patients with KD, apart from intensive care unit admission rate, adiposity category was not associated with laboratory test features or outcomes. For patients with MIS-C, higher adiposity category was associated with worse laboratory test values and outcomes, including a greater likelihood of shock, intensive care unit admission and inotrope requirement, and increased inflammatory markers, creatinine levels, and alanine aminotransferase levels. Adiposity category was not associated with coronary artery abnormalities for either MIS-C or KD. Conclusions and Relevance: In this international cohort study, obesity was more prevalent for patients with MIS-C vs KD, and associated with more severe presentation, laboratory test features, and outcomes. These findings suggest that obesity as a comorbid factor should be considered at the clinical presentation in children with MIS-C.

Cardiac Magnetic Resonance Imaging in Individuals With Prenatal Alcohol Exposure.

Background: Prenatal alcohol exposure (PAE) has teratogenic effects on numerous body systems including the heart. However, research magnetic resonance imaging (MRI) studies in humans with PAE have thus far been limited to the brain. This study aims to use MRI to examine heart structure and function, brain volumes, and body composition in children and adolescents with PAE. Methods: Heart, brain, and abdominal 3T MRI of 17 children, adolescents, and young adults with PAE and 53 unexposed controls was acquired to measure: (1) left ventricular ejection fraction, end-diastolic volume, end-systolic volume, stroke volume, cardiac output, longitudinal strain, circumferential strain, and heart mass; (2) total brain, cerebellum, white matter, grey matter, caudate, thalamus, putamen, and globus pallidus volumes; and (3) subcutaneous fat, visceral fat, muscle fat, and muscle (body composition). Results: Cardiac MRI revealed no abnormalities in the PAE group on evaluation by a paediatric cardiologist and by statistical comparison with a control group. Cardiac parameters in both groups were in line with previous reports, including expected sex- and age-related differences. Cerebellum, caudate, and globus pallidus volumes were all smaller. Body mass index and subcutaneous fat percent were higher in females with PAE relative to control females, but lower in males with PAE relative to control males. Conclusions: Children with PAE did not have abnormalities in MRI-derived measures of cardiac structure or function despite smaller brain volumes and sex-specific differences in body composition relative to healthy controls.

Contexte: L'exposition prénatale à l'alcool (EPA) engendre des effets tératogènes dans de nombreux systèmes et organes du corps humain, notamment le cœur. Cependant, la recherche à l'aide de l'imagerie par résonance magnétique (IRM) chez des humains ayant des antécédents d'EPA s'est limitée aux effets sur le cerveau jusqu'à maintenant. Cette étude vise à utiliser l'IRM pour examiner la fonction et la structure du cœur, le volume de diverses parties du cerveau ainsi que la composition corporelle chez des enfants et des adolescents ayant des antécédents d'EPA. Méthodologie: Chez 17 enfants, adolescents et jeunes adultes ayant été exposés à l'alcool au stade prénatal et chez 53 personnes n'ayant pas d'antécédents d'EPA, des images du cœur, du cerveau et de l'abdomen ont été acquises par la technique d'IRM 3T afin de mesurer : i) la fraction d'éjection du ventricule gauche, le volume télédiastolique, le volume télésystolique, le volume de sang éjecté, le débit cardiaque, la déformation longitudinale, la déformation circonférentielle et la masse cardiaque; ii) les volumes du cerveau en entier, du cervelet, de la substance blanche, de la substance grise, du noyau caudé, du thalamus, du putamen et du globus pallidus; et iii) le pourcentage de tissu adipeux contenu sous la peau, dans les viscères et dans les muscles ainsi que le pourcentage de muscles (composition corporelle). Résultats: Les images obtenues par l'IRM cardiaque n'ont pas révélé d'anomalies chez le groupe ayant des antécédents d'EPA après évaluation par un cardiologue pédiatrique et comparaison statistique avec le groupe témoin. Les paramètres cardiaques mesurés chez les deux groupes reflétaient les données ayant été précédemment rapportées, y compris les attentes liées aux différences quant au sexe et à l'âge. Les volumes du cervelet, du noyau caudé et du globus pallidus étaient diminués chez les personnes ayant des antécédents d'EPA. Alors que l'indice de masse corporelle et le pourcentage de tissu adipeux sous-cutané étaient plus élevés chez les personnes de sexe féminin ayant des antécédents d'EPA que chez les personnes de sexe féminin appartenant au groupe témoin, ces mêmes paramètres se trouvaient diminués chez les personnes de sexe masculin ayant des antécédents d'EPA comparativement aux personnes de sexe masculin appartenant au groupe témoin. Conclusions: Chez les enfants ayant des antécédents d'EPA, les mesures de la fonction et de la structure cardiaques dérivées des données de l'IRM ne présentaient pas d'anomalies, bien qu'une diminution du volume de certaines parties du cerveau et des différences dans la composition corporelle propres au sexe aient été observées dans ce groupe comparativement aux personnes en santé appartenant au groupe témoin.

Regional Elevation of Liver T1 in Fontan Patients.

Background: Fontan-associated liver disease (FALD) is characterized by hepatic congestion and progressive hepatic fibrosis in patients with the Fontan operation. This condition is generally clinically silent until late, necessitating techniques for early detection. Liver T1 mapping has been used to screen for FALD, but without consideration of regional variations in T1 values. Methods: Liver T1 measured with a liver-specific T1 mapping sequence (PROFIT1) in Fontan patients was compared with cohorts of patients with biventricular congenital heart disease (BiV-CHD) and controls with normal cardiac function and anatomy. Results: Liver T1 was significantly elevated in the Fontan cohort (n = 20) compared with patients with BiV-CHD (n = 12) and controls (n = 9) (781, 678, and 675 milliseconds, respectively; P < 0.001), with a consistent pattern of significantly elevated T1 values in the peripheral compared with central liver regions (ΔT1 = 54, 2, and 11 milliseconds; P < 0.001). PROFIT1 also yielded simultaneous T2∗ maps and fat fraction values that were similar in all groups. Fontan liver T1 values were also significantly elevated as compared with BiV-CHD and controls as measured with the cardiac (modified Look-Locker inversion) acquisitions (728, 583, and 583 milliseconds, respectively; P < 0.001) and values correlated with PROFIT1 liver T1 (R = 0.87, P < 0.001). Conclusions: Fontan patients have globally increased liver T1 values and consistent spatial variations, with higher values in the peripheral liver regions as compared with spatially uniform values in BiV-CHD and controls. The spatial patterns may provide insight into the progression of FALD. Liver T1 mapping studies should include uniform spatial coverage to avoid bias based on slice locations in this population.

Contexte: L'hépatopathie associée à une intervention de Fontan (FALD, pour Fontan-associated liver disease) se caractérise par une congestion hépatique et une fibrose hépatique évolutive chez les patients qui ont subi une intervention de Fontan. Il s'agit d'un état pathologique silencieux en début de progression, pour lequel des techniques de détection précoce sont requises. La cartographie T1 du foie est utilisée pour le dépistage de la FALD, mais sans que les variations locales des valeurs obtenues soient prises en compte. Méthodologie: Des valeurs T1 hépatiques ont été mesurées avec une séquence cartographique conçue pour le foie (PROFIT1) chez des patients qui ont subi une intervention de Fontan. Ces valeurs ont été comparées à celles d'une cohorte de patients atteints de cardiopathie congénitale biventriculaire (CC-BiV) et à celles de témoins dont l'anatomie et la fonction cardiaques étaient normales. Résultats: Les valeurs T1 hépatiques étaient significativement plus élevées chez les patients ayant subi une intervention de Fontan (n = 20) que chez les patients atteints de CC-BiV (n = 12) et chez les témoins (n = 9) (781 ms, 678 ms, 675 ms, p < 0,001), et ces valeurs tendaient à être plus élevées dans les régions périphériques que dans les régions centrales du foie (ΔT1 = 54 ms, 2 ms, 11 ms, p < 0,001). La séquence PROFIT1 a aussi permis l'obtention des valeurs de cartographie T2∗ et de teneur en matières grasses dans le foie, et ces valeurs étaient comparables pour tous les groupes. L'utilisation d'une séquence cardiaque (MOLLI, pour modified Lock-Locker inversion) a également engendré des valeurs T1 hépatiques significativement plus élevées chez les patients ayant subi l'intervention de Fontan que chez les patients atteints de CC-BiV et les témoins (728 ms, 583 ms, 583 ms, p < 0,001). Ces valeurs étaient par ailleurs corrélées avec les valeurs T1 hépatiques obtenues par la séquence PROFIT1 (R = 0,87, p < 0,001). Conclusions: Dans l'ensemble, les patients ayant subi l'intervention de Fontan présentaient des valeurs T1 hépatiques élevées accompagnées de variations spatiales. Les valeurs périphériques étaient systématiquement plus élevées, tandis que celles obtenues chez les patients atteints de CC-BiV et chez les témoins étaient uniformes. Les tendances qui sous-tendent ces variations spatiales pourraient fournir des pistes pour mieux comprendre la progression de la FALD. Enfin, les études de cartographie T1 hépatiques dans cette population devraient couvrir uniformément le foie pour éviter les biais liés à la coupe.

A germ-free humanized mouse model shows the contribution of resident microbiota to human-specific pathogen infection.

Germ-free (GF) mice, which are depleted of their resident microbiota, are the gold standard for exploring the role of the microbiome in health and disease; however, they are of limited value in the study of human-specific pathogens because they do not support their replication. Here, we develop GF mice systemically reconstituted with human immune cells and use them to evaluate the role of the resident microbiome in the acquisition, replication and pathogenesis of two human-specific pathogens, Epstein-Barr virus (EBV) and human immunodeficiency virus (HIV). Comparison with conventional (CV) humanized mice showed that resident microbiota enhance the establishment of EBV infection and EBV-induced tumorigenesis and increase mucosal HIV acquisition and replication. HIV RNA levels were higher in plasma and tissues of CV humanized mice compared with GF humanized mice. The frequency of CCR5+ CD4+ T cells throughout the intestine was also higher in CV humanized mice, indicating that resident microbiota govern levels of HIV target cells. Thus, resident microbiota promote the acquisition and pathogenesis of two clinically relevant human-specific pathogens.

T1 mapping of the myocardium and liver in the single ventricle population.

BACKGROUND: Fontan associated liver disease (FALD) is an increasingly recognized complication of the single ventricle circulation characterized by hepatic venous congestion leading to hepatic fibrosis. Within the Fontan myocardium, fibrotic myocardial remodeling may occur and lead to ventricular dysfunction. Magnetic resonance imaging (MRI) T1 mapping can characterize both myocardial and liver properties. OBJECTIVE: The aim of this study was to compare myocardial and liver T1 between single ventricle patients with and without a Fontan and biventricular controls. MATERIALS AND METHODS: A retrospective study of 3 groups of patients: 16 single ventricle patients before Fontan (SVpre 2 newborns, 9 pre-Glenn, 5 pre-Fontan, 31% single right ventricle [SRV]), 16 Fontans (56% SRV) and 10 repaired d-transposition of the great arteries (TGA). Native modified Look-Locker inversion T1 times were measured in the myocardium and liver. Cardiac MRI parameters, myocardial and liver T1 values were compared in the three groups. Correlations were assessed between liver T1 and cardiac parameters. RESULTS: Myocardial T1 was higher in SVpre (1,056 ± 48 ms) and Fontans (1,047 ± 41 ms) compared to TGA (1,012 ± 48 ms, P < 0.05). Increased liver T1 was found in both SVpre (683 ± 82 ms) and Fontan (727 ± 49 ms) patients compared to TGA patients (587 ± 58 ms, P < 0.001). There was no difference between single left ventricle (SLV) versus SRV myocardial or liver T1. Liver T1 showed moderate correlations with myocardial T1 (r = 0.48, confidence interval [CI] 0.26-0.72) and ejection fraction (r = -0.36, CI -0.66-0.95) but not with other volumetric parameters. CONCLUSION: Increased liver T1 at both pre- and post-Fontan stages suggests there are intrinsic liver abnormalities early in the course of single ventricle palliation. Increased myocardial T1 and its relationship to liver T1 suggest a combination of edema from passive venous congestion and/or myocardial fibrosis occurring in this population. Liver T1 may provide an earlier marker of liver disease warranting further study.

HIV co-infection augments EBV-induced tumorigenesis in vivo.

In most individuals, EBV maintains a life-long asymptomatic latent infection. However, EBV can induce the formation of B cell lymphomas in immune suppressed individuals including people living with HIV (PLWH). Most individuals who acquire HIV are already infected with EBV as EBV infection is primarily acquired during childhood and adolescence. Although antiretroviral therapy (ART) has substantially reduced the incidence of AIDS-associated malignancies, EBV positive PLWH are at an increased risk of developing lymphomas compared to the general population. The direct effect of HIV co-infection on EBV replication and EBV-induced tumorigenesis has not been experimentally examined. Using a humanized mouse model of EBV infection, we demonstrate that HIV co-infection enhances systemic EBV replication and immune activation. Importantly, EBV-induced tumorigenesis was augmented in EBV/HIV co-infected mice. Collectively, these results demonstrate a direct effect of HIV co-infection on EBV pathogenesis and disease progression and will facilitate future studies to address why the incidence of certain types of EBV-associated malignancies are stable or increasing in ART treated PLWH.

Improved accuracy and precision with three-parameter simultaneous myocardial T1 and T2 mapping using multiparametric SASHA.

PURPOSE: To develop and validate a three-parameter model for improved precision multiparametric SAturation-recovery single-SHot Acquisition (mSASHA) cardiac T1 and T2 mapping with high accuracy in a single breath-hold. METHODS: The mSASHA acquisition consists of nine images of variable saturation recovery and T2 preparation in 11 heartbeats with T1 and T2 values calculated using a three-parameter model. It was validated in simulations and phantoms at 3 T with comparison to a four-parameter joint T1 -T2 technique. The mSASHA acquisition was compared with MOLLI, SASHA, and T2 -prepared balanced SSFP in 10 volunteers. RESULTS: The mSASHA technique had high accuracy in phantoms compared to spin echo, with -0.2 ± 0.3% T1 error and -2.4 ± 1.3% T2 error. The mSASHA coefficient of variation in phantoms for T1 was similar to MOLLI (0.7 ± 0.2% for both) and T2 -prepared balanced SSFP for T2 (1.3 ± 0.7% vs 1.4 ± 0.3%, adjusted p > .05 for both). In simulations, three-parameter mSASHA had higher precision than four-parameter joint T1 -T2 for both T1 and T2 (46% and 11% reductions in T1 and T2 interquartile range for native myocardium). In vivo myocardial mSASHA T1 was similar to SASHA (1523 ± 18 ms vs 1520 ± 18 ms) with similar coefficient of variation to both MOLLI and SASHA (3.3 ± 0.6% vs 3.1 ± 0.6% and 3.3 ± 0.5% respectively, adjusted p > .05 for all). Myocardial mSASHA T2 was 37.1 ± 1.1 ms with similar precision to T2 -prepared balanced SSFP (6.7 ± 1.7% vs 6.0 ± 1.6%, adjusted p > .05). CONCLUSION: Three-parameter mSASHA provides high-accuracy cardiac T1 and T2 quantification in a single breath-hold with similar precision to MOLLI and T2 -prepared balanced SSFP. Further study is required to both establish normative values and demonstrate clinical utility in patient populations.

Cardiac and cardiometabolic phenotyping of trastuzumab-mediated cardiotoxicity: a secondary analysis of the MANTICORE trial.

AIMS: An improved understanding of the pathophysiology of trastuzumab-mediated cardiotoxicity is required to improve outcomes of patients with human epidermal growth factor receptor 2 (HER2)-positive breast cancer. We aimed to characterize the cardiac and cardiometabolic phenotype of trastuzumab-mediated toxicity and potential interactions with cardiac pharmacotherapy. METHODS AND RESULTS: This study was an analysis of serial magnetic resonance imaging (MRI) and circulating biomarker data acquired from patients with HER2-positive early-stage breast cancer participating in a randomized-controlled clinical trial for the pharmaco-prevention of trastuzumab-associated cardiotoxicity. Circulating biomarkers (B-type natriuretic peptide, troponin I, MMP-2 and -9, GDF-15, neuregulin-1, and IGF-1) and MRI of cardiac structure and function and abdominal fat distribution were acquired prior to trastuzumab, post-cycle 4 and post-cycle 17. Ninety-four participants (51 ± 8 years) completed the study with 30 on placebo, 33 on perindopril, and 31 on bisoprolol. Post-cycle 4, global longitudinal strain deteriorated from baseline in both placebo (+2.0 ± 2.7%, P = 0.002) and perindopril (+0.9 ± 2.5%, P = 0.04), but not with bisoprolol (-0.2 ± 2.1%, P = 0.55). In all groups combined, extracellular volume fraction and GDF-15 increased post-cycle 4 (+1.3 ± 4.4%, P = 0.004; +130 ± 150%, P ≤ 0.001, respectively). However, no significant change in troponin I was detected throughout trastuzumab. In all groups combined, visceral and intermuscular fat volume increased post-cycle 4 (+7 ± 17%, P = 0.02, +8 ± 23%, P = 0.02, respectively), while muscle volume and IGF-1 decreased from post-cycle 4 to 17 (-2 ± 10%, P = 0.008, -18 ± 28%, P < 0.001, respectively). CONCLUSION: Trastuzumab results in impaired cardiac function and early myocardial inflammation. Trastuzumab is also associated with deleterious changes to the cardiometabolic phenotype which may contribute to the increased cardiovascular risk in this population.

Cardiac remodelling predicts outcome in patients with chronic heart failure.

AIMS: Surveillance imaging is often used to detect remodelling, a change in cardiac geometry, and/or function; however, there are limited data in patients with chronic heart failure (HF). We sought to characterize cardiac remodelling in patients with chronic HF and evaluate its association with outcome. METHODS AND RESULTS: A prospective cohort of patients at risk for HF or with chronic HF underwent cardiac magnetic resonance (CMR) at baseline and 1 year. Ventricular function, volumes, mass, left atrial volume, global longitudinal strain, and myocardial scar were measured. The primary outcome was a composite of death or cardiovascular hospitalization up to 5 years from the 1 year scan. Cox regression was used to identify 1 year CMR predictors of outcome after adjusting for baseline risk. A total of 262 patients (median age 68 years, 57% males) including 96 at risk for HF, 97 with HF and preserved ejection fraction, and 69 with HF and reduced ejection fraction were included. In the patients with HF, 55 events were identified during follow-up. After adjustment for baseline clinical risk, Cox proportion hazard regressions only identified 1 year change in left ventricular (LV) mass index as a CMR predictor of outcome, adjusted hazard ratio 1.21 (1.02, 1.44) per 10% increase, P = 0.031. Cardiac remodelling defined as a 1 year change in LV mass index ≥15% was observed in 35% of patients with HF. Patients with adverse remodelling of LV mass index had more events on Kaplan-Meier analyses compared to those with no remodelling, log-rank P = 0.004 for overall cohort, P = 0.035 for heart failure with preserved ejection fraction and P = 0.035 for heart failure and reduced ejection fraction. CONCLUSIONS: Cardiac remodelling is common during serial CMR assessment of patients with chronic HF. Change in LV mass predicted long-term outcomes whereas change in left ventricular ejection fraction did not.

Effect of anthracycline therapy on myocardial function and markers of fibrotic remodelling in childhood cancer survivors.

AIMS: Anthracyclines are a cornerstone of paediatric cancer treatment. We aimed to quantify myocardial cardiac magnetic resonance (CMR) native T1 (NT1) and extracellular volume fraction (ECV) as markers of fibrosis in a cohort of childhood cancer survivors (CCS). METHODS AND RESULTS: A cohort of CCS in remission underwent CMR T1 mapping. Diastolic function was assessed by echocardiography. Results were compared to a cohort of normal controls of similar age and gender. Fifty-five CCS and 46 controls were included. Both groups had similar mean left ventricular (LV) NT1 values (999 ± 36 vs. 1007 ± 32 ms, P = 0.27); ECV was higher (25.6 ± 6.9 vs. 20.7 ± 2.4%, P = 0.003) and intracellular mass was lower (37.5 ± 8.4 vs. 43.3 ± 9.9g/m2, P = 0.02) in CCS. The CCS group had lower LV ejection fraction (EF) and LV mass index with otherwise normal diastolic function in all but one patient. The proportion of subjects with elevated ECV compared to controls did not differ between subgroups with normal or reduced LV EF (22% vs. 28%; P = 0.13) and no correlations were found between LVEF and ECV. While average values remained within normal range, mitral E/E' (6.6 ± 1.6 vs. 5.9 ± 0.9, P = 0.02) was higher in CCS. Neither NT1 nor ECV correlated with diastolic function indices or cumulative anthracycline dose. CONCLUSIONS: There is evidence for mild diffuse extracellular volume expansion in some asymptomatic CCS; myocyte loss could be part of the mechanism, accompanied by subtle changes in systolic and diastolic function. These findings suggest mild myocardial damage and remodelling after anthracycline treatment in some CCS which requires continued monitoring.

Simultaneous proton density fat-fraction and R2∗ imaging with water-specific T1 mapping (PROFIT1 ): application in liver.

PURPOSE: To describe and validate a simultaneous proton density fat-fraction (PDFF) imaging and water-specific T1 mapping (T1(Water) ) approach for the liver (PROFIT1 ) with R2∗ mapping and low sensitivity to B1+ calibration or inhomogeneity. METHODS: A multiecho gradient-echo sequence, with and without saturation preparation, was designed for simultaneous imaging of liver PDFF, R2∗ , and T1(Water) (three slices in ~13 seconds). Chemical-shift-encoded MRI processing yielded fat-water separated images and R2∗ maps. T1(Water)  calculation utilized saturation and nonsaturation-recovery water-separated images. Several variable flip angle schemes across k-space (increasing flip angles in sequential RF pulses) were evaluated for minimization of T1 weighting, to reduce the B1+ dependence of T1(Water)  and PDFF (reduced flip angle dependence). T1(Water)  accuracy was validated in mixed fat-water phantoms, with various PDFF and T1 values (3T). In vivo application was illustrated in five volunteers and five patients with nonalcoholic fatty liver disease (PDFF, T1(Water) , R2∗ ). RESULTS: A sin3 (θ) flip angle pattern (0 < Î¸ < π/2 over k-space) yielded the largest PROFIT1 signal yield with negligible B1+ dependence for both T1(Water) and PDFF. Mixed fat-water phantom experiments illustrated excellent agreement between PROFIT1 and gold-standard spectroscopic evaluation of PDFF and T1(Water)  (<1% T1 error). In vivo PDFF, T1(Water) , and R2∗ maps illustrated independence of the PROFIT1 values from B1+ inhomogeneity and significant differences between volunteers and patients with nonalcoholic fatty liver disease for T1(Water) (927 ± 56 ms vs. 1033 ± 23 ms; P < .05) and PDFF (2.0% ± 0.8% vs. 13.4% ± 5.0%, P < .05).  R2∗ was similar between groups. CONCLUSION: The PROFIT1 pulse sequence provides fast simultaneous quantification of PDFF, T1(Water) , and R2∗ with minimal sensitivity to B1+ miscalibration or inhomogeneity.

Layer-specific strain in patients with heart failure using cardiovascular magnetic resonance: not all layers are the same.

BACKGROUND: Global longitudinal strain (GLS), most commonly measured at the endocardium, has been shown to be superior to left ventricular (LV) ejection fraction (LVEF) for the identification of systolic dysfunction and prediction of outcomes in heart failure (HF). We hypothesized that strains measured at different myocardial layers (endocardium = ENDO, epicardium = EPI, average = AVE) will have distinct diagnostic and predictive performance for patients with HF. METHODS: Layer-specific GLS, layer-specific global circumferential strain (GCS) and global radial strain (GRS) were evaluated by cardiovascular magnetic resonance imaging (CMR) feature tracking in the Alberta HEART study. A total of 453 subjects consisted of healthy controls (controls, n = 77), at-risk for HF (at-risk, n = 143), HF with preserved ejection fraction (HFpEF, n = 87), HF with mid-range ejection fraction (HFmrEF, n = 88) and HF with reduced ejection fraction (HFrEF, n = 58). For outcomes analysis, CMR-derived imaging parameters were adjusted with a base model that included age and N-terminal prohormone of b-type natriuretic peptide (NT-proBNP) to test their independent association with 5-year all-cause mortality. RESULTS: GLS_EPI distinguished all groups with preserved LVEF (controls - 16.5 ± 2.4% vs. at-risk - 15.5 ± 2.7% vs. HFpEF - 14.1 ± 3.0%, p < 0.001) while GLS_ENDO and all GCS (all layers) were similar among these groups. GRS was reduced in HFpEF (41.1 ± 13.8% versus 48.9 ± 10.7% in controls, p < 0.001) and the difference between GLS_EPI and GLS_ENDO were significantly larger in HFpEF as compared to controls. Within the preserved LVEF groups, reduced GRS and GLS_EPI were significantly associated with increased LV mass (LVM) and LVM/LV end-diastolic volume EDV (concentricity). In multivariable analysis, only GLS_AVE and GRS predicted 5-year all-cause mortality (all ps < 0.05), with the strongest association with 5-year all-cause mortality by Akaike Information Criterion analysis and significant incremental value for outcomes prediction beyond LVEF or GLS_ENDO by the likelihood ratio test. CONCLUSION: Global strains measured on endocardium, epicardium or averaged across the wall thickness are not equivalent for the identification of systolic dysfunction or outcomes prediction in HF. The endocardium-specific strains were shown to have poorest all-around performance. GLS_AVE and GRS were the only CMR parameters to be significantly associated with 5-year all-cause mortality in multivariable analysis. GLS_EPI and GRS, as well as the difference in endocardial and epicardial strains, were sensitive to systolic dysfunction among HF patients with normal LVEF (> 55%), in whom lower strains were associated with increased concentricity.

Normative Data for Myocardial Native T1 and Extracellular Volume Fraction in Children.

PURPOSE: To establish normative data for myocardial T1, including extracellular volume (ECV) fraction, in healthy children. MATERIALS AND METHODS: In this retrospective, single-center study, T1 mapping data were collected from 48 healthy pediatric patients (14 years ± 3 [standard deviation]; range, 9-18 years; 27 of 48 [56%] male) referred for cardiac screening 1.5-T MRI between 2014 and 2017. T1 relaxometry was performed using a 5(number of heartbeats [nHB])3 modified Look-Locker inversion recovery (MOLLI) sequence, where nHB was three to five heartbeats depending on the heart rate, and was repeated 15 minutes following the administration of 0.2 mmol per kilogram of body weight of gadobenate dimeglumine, with 19 patients receiving contrast material. T1 values were calculated using a curve-fitting algorithm on average region-of-interest signal and corrected for imperfect inversion pulse efficiency. Comparisons within patients were performed with paired Student t test, between groups with unpaired Student t test or Mann-Whitney U test, and linear regression was performed to examine for associations with other variables. RESULTS: Average native T1 was 1008 msec ± 31, with a nonsignificant increase in females (1017 msec ± 27 vs 1001 msec ± 33, P = .066). Average ECV was 20.8% ± 2.4, with a nonsignificant increase in values in females (21.7% ± 1.9 vs 20.0% ± 2.6, P = .123). T1 and ECV values were increased in the septum versus the free wall. CONCLUSION: Normative data are presented for myocardial native T1 and ECV using the MOLLI T1 mapping sequence at 1.5 T.Supplemental material is available for this article.© RSNA, 2020.

Small molecule screening identifies inhibitors of the Epstein-Barr virus deubiquitinating enzyme, BPLF1.

Herpesviral deubiquitinating enzymes (DUBs) were discovered in 2005, are highly conserved across the family, and are proving to be increasingly important players in herpesviral infection. EBV's DUB, BPLF1, is known to regulate both cellular and viral target activities, yet remains largely unstudied. Our work has implicated BPLF1 in a wide range of processes including infectivity, viral DNA replication, and DNA repair. Additionally, knockout of BPLF1 delays and reduces human B-cell immortalization and lymphoma formation in humanized mice. These findings underscore the importance of BPLF1 in viral infectivity and pathogenesis and suggest that inhibition of EBV's DUB activity may offer a new approach to specific therapy for EBV infections. We set out to discover and characterize small molecule inhibitors of BPLF1 deubiquitinating activity through high-throughput screening. An initial small pilot screen resulted in discovery of 10 compounds yielding >80% decrease in BPLF1 DUB activity at a 10 µM concentration. Follow-up dose response curves of top hits identified several compounds with an IC50 in the low micromolar range. Four of these hits were tested for their ability to cleave ubiquitin chains as well as their effects on viral infectivity and cell viability. Further characterization of the top hit, commonly known as suramin was found to not be selective yet decreased viral infectivity by approximately 90% with no apparent effects on cell viability. Due to the conserved nature of Herpesviral deubiquitinating enzymes, identification of an inhibitor of BPLF1 may prove to be an effective and promising new avenue of therapy for EBV and other herpesviral family members.

Quantification of lung water in heart failure using cardiovascular magnetic resonance imaging.

BACKGROUND: Pulmonary edema is a cardinal feature of heart failure but no quantitative tests are available in clinical practice. The goals of this study were to develop a simple cardiovascular magnetic resonance (CMR) approach for lung water quantification, to correlate CMR derived lung water with intra-cardiac pressures and to determine its prognostic significance. METHODS: Lung water density (LWD, %) was measured using a widely available single-shot fast spin-echo acquisition in two study cohorts. Validation Cohort: LWD was compared to left ventricular end-diastolic pressure or pulmonary capillary wedge pressure in 19 patients with heart failure undergoing cardiac catheterization. Prospective Cohort: LWD was measured in 256 subjects, including 121 with heart failure, 82 at-risk for heart failure and 53 healthy controls. Clinical outcomes were evaluated up to 1 year. RESULTS: Within the validation cohort, CMR LWD correlated to invasively measured left-sided filling pressures (R = 0.8, p < 0.05). In the prospective cohort, mean LWD was 16.6 ± 2.1% in controls, 17.9 ± 3.0% in patients at-risk and 19.3 ± 5.4% in patients with heart failure, p < 0.001. In patients with or at-risk for heart failure, LWD >  20.8% (mean + 2 standard deviations of healthy controls) was an independent predictor of death, hospitalization or emergency department visit within 1 year, hazard ratio 2.4 (1.1-5.1, p = 0.03). CONCLUSIONS: In patients with heart failure, increased CMR-derived lung water is associated with increased intra-cardiac filling pressures, and predicts 1 year outcomes. LWD could be incorporated in standard CMR scans.

Inhibition of UCH-L1 Deubiquitinating Activity with Two Forms of LDN-57444 Has Anti-Invasive Effects in Metastatic Carcinoma Cells.

Normally ubiquitin C-terminal hydrolase L1 (UCH-L1) is expressed in the central nervous and reproductive systems of adults, but its de novo expression has been detected in many human cancers. There is a growing body of evidence that UCH-L1 de-ubiquitinating (DUB) activity plays a major pro-metastatic role in certain carcinomas. Here we tested anti-metastatic effects of the small-molecule inhibitor of UCH-L1 DUB activity, LDN-57444, in cell lines from advanced oral squamous cell carcinoma (OSCC) as well as invasive nasopharyngeal (NP) cell lines expressing the major pro-metastatic gene product of Epstein-Barr virus (EBV) tumor virus, LMP1. To overcome the limited aqueous solubility of LDN-57444 we developed a nanoparticle formulation of LDN-57444 by incorporation of the compound in polyoxazoline micellear nanoparticles (LDN-POx). LDN-POx nanoparticles were equal in effects as the native compound in vitro. Our results demonstrate that inhibition of UCH-L1 DUB activity with LDN or LDN-POx inhibits secretion of exosomes and reduces levels of the pro-metastatic factor in exosomal fractions. Both forms of UCH-L1 DUB inhibitor suppress motility of metastatic squamous carcinoma cells as well as nasopharyngeal cells expressing EBV pro-metastatic Latent membrane protein 1 (LMP1) in physiological assays. Moreover, treatment with LDN and LDN-POx resulted in reduced levels of pro-metastatic markers, a decrease of carcinoma cell adhesion, as well as inhibition of extra-cellular vesicle (ECV)-mediated transfer of viral invasive factor LMP1. We suggest that soluble inhibitors of UCH-L1 such as LDN-POx offer potential forms of treatment for invasive carcinomas including EBV-positive malignancies.

Increased extracellular volume in the liver of pediatric Fontan patients.

BACKGROUND: Patients with single ventricle physiology are at increased risk for developing liver fibrosis. Its extent and prevalence in children with bidirectional cavopulmonary connection (BCPC) and Fontan circulation are unclear. Extracellular volume fraction (ECV), derived from cardiovascular magnetic resonance (CMR) and T1 relaxometry, reflect fibrotic remodeling and/or congestion in the liver. The aim of this study was to investigate whether pediatric patients with single ventricle physiology experience increased native T1 and ECV as markers of liver fibrosis/congestion. METHODS: Hepatic native T1 times and ECV, using a cardiac short axis modified Look-Locker inversion recovery sequence displaying the liver, were measured retrospectively in children with BCPC- and Fontan circulations and compared to pediatric controls. RESULTS: Hepatic native T1 time were increased in Fontan patients (n = 62, 11.4 ± 4.4 years, T1 762 ± 64 ms) versus BCPC patients (n = 20, 2.8 ± 0.9 years, T1 645 ± 43 ms, p = 0.04). Both cohorts had higher T1 than controls (n = 44, 13.7 ± 2.9 years, T1 604 ± 54 ms, p < 0.001 for both). ECV was 41.4 ± 4.8% in Fontan and 36.4 ± 4.8% in BCPC patients, respectively (p = 0.02). In Fontan patients, T1 values correlated with exposure to cardiopulmonary bypass time (R = 0.3, p = 0.02), systolic and end diastolic volumes (R = 0.3, p = 0.04 for both) and inversely with oxygen saturations and body surface area (R = -0.3, p = 0.04 for both). There were no demonstrable associations of T1 or ECV with central venous pressure or age after Fontan. CONCLUSION: Fontan and BCPC patients have elevated CMR markers suggestive of hepatic fibrosis and/or congestion, even at a young age. The tissue changes do not appear to be related to central venous pressures. TRIAL REGISTRATION: Retrospectively registered data.

Mapping versus source methods for quantifying myocardial T1 in controls and in repaired tetralogy of Fallot: interchangeability and reproducibility in children.

BACKGROUND: Myocardial T1 relaxometry can be performed by contouring on individual T1-weighted source images (source method) or on a single T1 map (mapping method). OBJECTIVE: This study compares (a) agreement between native T1 and extracellular volume results of the two methods and (b) interobserver reproducibility of the two methods in children without heart disease and those with tetralogy of Fallot (TOF). MATERIALS AND METHODS: We retrospectively analyzed pediatric patients (controls and those with repaired TOF) with cardiac magnetic resonance examinations including extracellular volume quantification using the modified Look-Locker inversion recovery (MOLLI) sequence. We compared native T1 and extracellular volume of the entire left ventricle and interventricular septum derived using the source and the mapping approaches. RESULTS: In the control group (n=25, median age 14.0 years, interquartile range [IQR] 11.5-16.5 years), the mapping method produced lower native T1 values than the source method in the interventricular septum (mean difference ± standard deviation [SD] = 12±15 ms, P<0.001). In the TOF group (n=50, median age 13.3 years, IQR 9.9-15.0 years), the mapping method produced lower values for native T1 and extracellular volume in the interventricular septum (mean difference 9±14 ms and 0.6±1.1%, P<0.001). In 6-12% of the children, differences were >3 standard deviations from the mean difference. Interobserver reproducibility between the two methods by intraclass correlation coefficients were clinically equivalent. CONCLUSION: T1 and extracellular volume values generated by the source and mapping methods show systematic differences and can vary significantly in an individual child, and thus cannot be used interchangeably in clinical practice. The source method might allow for easier detection and, in some cases, mitigation of artifacts that are not infrequent in children and can be difficult to appreciate on the T1 map.