Sacubitril/Valsartan in Pediatric Heart Failure (PANORAMA-HF): A Randomized, Multicenter, Double-Blind Trial.

BACKGROUND: Sacubitril/valsartan, an angiotensin receptor-neprilysin inhibitor (ARNI), is an established treatment for heart failure (HF) with reduced left ventricular ejection fraction. It has not been rigorously compared with angiotensin-converting enzyme inhibitors in children. PANORAMA-HF (Prospective Trial to Assess the Angiotensin Receptor Blocker Neprilysin Inhibitor LCZ696 Versus Angiotensin-Converting Enzyme Inhibitor for the Medical Treatment of Pediatric HF) is a randomized, double-blind trial that evaluated the pharmacokinetics and pharmacodynamics (PK/PD), safety, and efficacy of sacubitril/valsartan versus enalapril in children 1 month to <18 years of age with HF attributable to systemic left ventricular systolic dysfunction (LVSD). METHODS: Children with HF attributable to LVSD were randomized to sacubitril/valsartan versus enalapril to assess the efficacy and safety of sacubitril/valsartan at 52 weeks of follow-up. The primary end point of the study was to determine whether sacubitril/valsartan was superior to enalapril for the treatment of pediatric patients with HF attributable to systemic LVSD, assessed using a primary global rank end point consisting of ranking patients from worst to best on the basis of clinical events such as death, listing for urgent heart transplant, mechanical life support requirement, worsening HF, New York Heart Association (NYHA)/Ross class, Patient Global Impression of Severity (PGIS), and Pediatric Quality of Life Inventory physical functioning domain. The change from baseline to 52 weeks in NT-proBNP (N-terminal pro-B-type natriuretic peptide) was an exploratory end point. RESULTS: A total of 375 children (mean age, 8.1±5.6 years; 52% female) were randomized to sacubitril/valsartan (n=187) or enalapril (n=188). At week 52, no significant difference was observed between the 2 treatment arms in the global rank end point (Mann-Whitney probability, 0.52 [95% CI, 0.47-0.58]; Mann-Whitney odds, 0.91 [95% CI, 0.72-1.14]; P=0.42). At week 52, clinically meaningful reductions were observed in both treatment arms in NYHA/Ross, PGIS, Patient Global Impression of Change, and NT-proBNP, without significant differences between groups. Adverse events were similar between treatment arms (incidence: sacubitril/valsartan, 88.8%; enalapril, 87.8%), and the safety profile of sacubitril/valsartan was acceptable in children. CONCLUSIONS: In this study, sacubitril/valsartan did not show superiority over enalapril in the treatment of children with HF attributable to systemic LVSD using the prespecified global rank end point. However, both treatment arms showed clinically meaningful improvements over 52 weeks. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT02678312.

Low pre-albumin but not thiamine predicts cognitive deficits in adolescents post-Fontan and healthy controls.

BACKGROUND: Low pre-albumin, body mass index, and thiamine levels have been associated with poor nutritional status and cognitive/memory deficits in adult heart failure patients. However, the relationship of these nutritional/dietary intake biomarkers to cognition has not been assessed in adolescents post-Fontan procedure and healthy controls. METHODS: This is a cross-sectional study. Adolescents (14-21 years of age) post-Fontan completion were recruited from paediatric cardiology clinics and controls from the community. The Montreal Cognitive Assessment was administered (normal ≥ 26), and blood draw (thiamine [normal 70-110 nmol/L] and pre-albumin levels [adolescent normal 23-45 mg/dL]) and the Thiamine Food Frequency Questionnaire were completed by all participants. RESULTS: Seventy subjects, 40 post-Fontan (mean age 16 ± 1.6, female 51%, Hispanic 44%, hypoplastic left heart syndrome 26%) and 30 controls (mean age 16.8 ± 1.9, female 52%, Hispanic 66%), were participated. Post-Fontan group had lower median total cognitive scores (23 versus 29, p < 0.001), pre-albumin levels (23 versus 27, p = 0.013), and body mass index (20 versus 24, p = 0.027) than controls. Post-Fontan group had higher thiamine levels than controls (127 versus 103, p = 0.033). Lower pre-albumin levels (< 23) and underweight body mass index were associated with abnormal total cognitive scores (p = 0.030). Low pre-albumin level (p = .038) was an independent predictor of worse cognition. CONCLUSION: Lower pre-albumin was an independent predictor for worse cognition in adolescents post-Fontan. Lower pre-albumin levels may reflect chronic liver changes or protein-losing enteropathy seen in Fontan physiology. These findings highlight the possibility for nutrition-induced cognitive changes.

High-Throughput Genomics Identify Novel FBN1/2 Variants in Severe Neonatal Marfan Syndrome and Congenital Heart Defects.

Fibrillin-1 and fibrillin-2, encoded by FBN1 and FBN2, respectively, play significant roles in elastic fiber assembly, with pathogenic variants causing a diverse group of connective tissue disorders such as Marfan syndrome (MFS) and congenital contractural arachnodactyly (CCD). Different genomic variations may lead to heterogeneous phenotypic features and functional consequences. Recent high-throughput sequencing modalities have allowed detection of novel variants that may guide the care for patients and inform the genetic counseling for their families. We performed clinical phenotyping for two newborn infants with complex congenital heart defects. For genetic investigations, we employed next-generation sequencing strategies including whole-genome Single-Nucleotide Polymorphism (SNP) microarray for infant A with valvular insufficiency, aortic sinus dilatation, hydronephrosis, and dysmorphic features, and Trio whole-exome sequencing (WES) for infant B with dextro-transposition of the great arteries (D-TGA) and both parents. Infant A is a term male with neonatal marfanoid features, left-sided hydronephrosis, and complex congenital heart defects including tricuspid regurgitation, aortic sinus dilatation, patent foramen ovale, patent ductus arteriosus, mitral regurgitation, tricuspid regurgitation, aortic regurgitation, and pulmonary sinus dilatation. He developed severe persistent pulmonary hypertension and worsening acute hypercapnic hypoxemic respiratory failure, and subsequently expired on day of life (DOL) 10 after compassionate extubation. Cytogenomic whole-genome SNP microarray analysis revealed a deletion within the FBN1 gene spanning exons 7-30, which overlapped with the exon deletion hotspot region associated with neonatal Marfan syndrome. Infant B is a term male prenatally diagnosed with isolated D-TGA. He required balloon atrial septostomy on DOL 0 and subsequent atrial switch operation, atrial septal defect repair, and patent ductus arteriosus ligation on DOL 5. Trio-WES revealed compound heterozygous c.518C>T and c.8230T>G variants in the FBN2 gene. Zygosity analysis confirmed each of the variants was inherited from one of the parents who were healthy heterozygous carriers. Since his cardiac repair at birth, he has been growing and developing well without any further hospitalization. Our study highlights novel FBN1/FBN2 variants and signifies the phenotype-genotype association in two infants affected with complex congenital heart defects with and without dysmorphic features. These findings speak to the importance of next-generation high-throughput genomics for novel variant detection and the phenotypic variability associated with FBN1/FBN2 variants, particularly in the neonatal period, which may significantly impact clinical care and family counseling.

Right Ventricular Function and T1-Mapping in Boys With Duchenne Muscular Dystrophy.

BACKGROUND: Clinical management of boys with Duchenne muscular dystrophy (DMD) relies on in-depth understanding of cardiac involvement, but right ventricular (RV) structural and functional remodeling remains understudied. PURPOSE: To evaluate several analysis methods and identify the most reliable one to measure RV pre- and postcontrast T1 (RV-T1) and to characterize myocardial remodeling in the RV of boys with DMD. STUDY TYPE: Prospective. POPULATION: Boys with DMD (N = 27) and age-/sex-matched healthy controls (N = 17) from two sites. FIELD STRENGTH/SEQUENCE: 3.0 T using balanced steady state free precession, motion-corrected phase sensitive inversion recovery and modified Look-Locker inversion recovery sequences. ASSESSMENT: Biventricular mass (Mi), end-diastolic volume (EDVi) and ejection fraction (EF) assessment, tricuspid annular excursion (TAE), late gadolinium enhancement (LGE), pre- and postcontrast myocardial T1 maps. The RV-T1 reliability was assessed by three observers in four different RV regions of interest (ROI) using intraclass correlation (ICC). STATISTICAL TESTS: The Wilcoxon rank sum test was used to compare RV-T1 differences between DMD boys with negative LGE(-) or positive LGE(+) and healthy controls. Additionally, correlation of precontrast RV-T1 with functional measures was performed. A P-value <0.05 was considered statistically significant. RESULTS: A 1-pixel thick RV circumferential ROI proved most reliable (ICC > 0.91) for assessing RV-T1. Precontrast RV-T1 was significantly higher in boys with DMD compared to controls. Both LGE(-) and LGE(+) boys had significantly elevated precontrast RV-T1 compared to controls (1543 [1489-1597] msec and 1550 [1402-1699] msec vs. 1436 [1399-1473] msec, respectively). Compared to healthy controls, boys with DMD had preserved RVEF (51.8 [9.9]% vs. 54.2 [7.2]%, P = 0.31) and significantly reduced RVMi (29.8 [9.7] g vs. 48.0 [15.7] g), RVEDVi (69.8 [29.7] mL/m2 vs. 89.1 [21.9] mL/m2 ), and TAE (22.0 [3.2] cm vs. 26.0 [4.7] cm). Significant correlations were found between precontrast RV-T1 and RVEF (ß = -0.48%/msec) and between LV-T1 and LVEF (ß = -0.51%/msec). DATA CONCLUSION: Precontrast RV-T1 is elevated in boys with DMD compared to healthy controls and is negatively correlated with RVEF. LEVEL OF EVIDENCE: 1 TECHNICAL EFFICACY: Stage 2.

Fontan-associated plastic bronchitis waitlist and heart transplant outcomes: A PHTS analysis.

Plastic bronchitis is a rare post-Fontan complication with limited treatment options. Heart transplantation has evolved as a potential curative option, but outcomes have not been well-defined. This study aims to assess contemporary waitlist and post-transplant outcomes in patients with plastic bronchitis. All Fontan patients were identified in the PHTS database (2010 - 2018). Waitlist and post-transplant outcomes were compared between Fontan patients with and without plastic bronchitis. Competing outcomes and Kaplan-Meier analyses were used to assess the impact of plastic bronchitis on waitlist and post-transplant survival. A secondary analysis excluded those with PLE from the comparison cohort. Of 645 Fontan patients listed for heart transplant, 69 (11%) had plastic bronchitis. At listing, patients with plastic bronchitis were younger (8.9 vs 11.1 years, P = .02), but had few other differences in baseline characteristics. A fewer Fontan patients with plastic bronchitis were listed in the more recent era (46 [15.4%] in 2010-2014 vs 23 [6.6%] in 2015-2018, P < .01). Overall, there was no difference in waitlist (P = .30) or post-transplant (P = .66) survival for Fontan patients with and without plastic bronchitis. The results were similar after excluding patients with PLE. Contrary to prior reports, this relatively large series showed that plastic bronchitis did not have a negative impact on survival to or after heart transplantation in Fontan patients. Our study also found a 50% reduction in listing in the current era, which may indicate evolution in management of Fontan patients.

Caudate nuclei volume alterations and cognition and mood dysfunctions in adolescents with single ventricle heart disease.

Adolescents with single ventricle heart disease (SVHD) exhibit mood and cognitive deficits, which may result from injury to the basal ganglia structures, including the caudate nuclei. However, the integrity of the caudate in SVHD adolescents is unclear. Our aim was to examine the global and regional caudate volumes, and evaluate the relationships between caudate volumes and cognitive and mood scores in SVHD and healthy adolescents. We acquired two high-resolution T1-weighted images from 23 SVHD and 37 controls using a 3.0-Tesla MRI scanner, as well as assessed mood (Patient Health Questionnaire-9 [PHQ-9]; Beck Anxiety Inventory [BAI]) and cognition (Montreal Cognitive Assessment [MoCA]; Wide Range Assessment of Memory and Learning-2; General Memory Index [GMI]) functions. Both left and right caudate nuclei were outlined, which were then used to calculate and compare volumes between groups using ANCOVA (covariates: age, gender, and head-size), as well as perform 3D surface morphometry. Partial correlations (covariates: age, gender, and head-size) were used to examine associations between caudate volumes, cognition, and mood scores in SVHD and controls. SVHD subjects showed significantly higher PHQ-9 and BAI scores, indicating more depressive and anxiety symptoms, as well as reduced GMI scores, suggesting impaired cognition, compared to controls. SVHD patients showed significantly reduced caudate volumes (left, 3,198.8 ± 490.1 vs. 3,605.0 ± 480.4 mm3 , p < 0.004; right, 3,162.1 ± 475.4 vs. 3,504.8 ± 465.9 mm3 , p < 0.011) over controls, and changes were localized in the rostral, mid-dorsolateral, and caudal areas. Significant negative correlations emerged between caudate volumes with PHQ-9 and BAI scores and positive correlations with GMI and MoCA scores in SVHD and controls. SVHD adolescents show significantly reduced caudate volumes, especially in sites that have projections to regulate mood and cognition, which may result from developmental and/or hypoxia-/ischemia-induced processes.

Reduced brain mammillary body volumes and memory deficits in adolescents who have undergone the Fontan procedure.

BACKGROUND: Adolescents with single ventricle heart disease (SVHD) who have undergone the Fontan procedure show cognitive/memory deficits. Mammillary bodies are key brain sites that regulate memory; however, their integrity in SVHD is unclear. We evaluated mammillary body (MB) volumes and their associations with cognitive/memory scores in SVHD and controls. METHODS: Brain MRI data were collected from 63 adolescents (25 SVHD; 38 controls) using a 3.0-Tesla MRI scanner. Cognition and memory were assessed using Montreal Cognitive Assessment (MoCA) and Wide Range Assessment of Memory and Learning 2. MB volumes were calculated and compared between groups (ANCOVA, covariates: age, sex, and total brain volume [TBV]). Partial correlations and linear regression were performed to examine associations between volumes and cognitive scores (covariates: age, sex, and TBV). RESULTS: SVHD group showed significantly lower MoCA and WRAML2 scores over controls. MB volumes were significantly reduced in SVHD over controls. After controlling for age, sex, and TBV, MB volumes correlated with MoCA and delayed memory recall scores in SVHD and controls. CONCLUSION: Adolescents with SVHD show reduced MB volumes associated with cognitive/memory deficits. Potential mechanisms of volume losses may include developmental and/or hypoxic/ischemic-induced processes. Providers should screen for cognitive deficits and explore possible interventions to improve memory.

T1-Mapping and extracellular volume estimates in pediatric subjects with Duchenne muscular dystrophy and healthy controls at 3T.

BACKGROUND: Cardiovascular disease is the leading cause of death in patients with Duchenne muscular dystrophy (DMD)-a fatal X-linked genetic disorder. Late gadolinium enhancement (LGE) imaging is the current gold standard for detecting myocardial tissue remodeling, but it is often a late finding. Current research aims to investigate cardiovascular magnetic resonance (CMR) biomarkers, including native (pre-contrast) T1 and extracellular volume (ECV) to evaluate the early on-set of microstructural remodeling and to grade disease severity. To date, native T1 measurements in DMD have been reported predominantly at 1.5T. This study uses 3T CMR: (1) to characterize global and regional myocardial pre-contrast T1 differences between healthy controls and LGE + and LGE- boys with DMD; and (2) to report global and regional myocardial post-contrast T1 values and myocardial ECV estimates in boys with DMD, and (3) to identify left ventricular (LV) T1-mapping biomarkers capable of distinguishing between healthy controls and boys with DMD and detecting LGE status in DMD. METHODS: Boys with DMD (N = 28, 13.2 ± 3.1 years) and healthy age-matched boys (N = 20, 13.4 ± 3.1 years) were prospectively enrolled and underwent a 3T CMR exam including standard functional imaging and T1 mapping using a modified Look-Locker inversion recovery (MOLLI) sequence. Pre-contrast T1 mapping was performed on all boys, but contrast was administered only to boys with DMD for post-contrast T1 and ECV mapping. Global and segmental myocardial regions of interest were contoured on mid LV T1 and ECV maps. ROI measurements were compared for pre-contrast myocardial T1 between boys with DMD and healthy controls, and for post-contrast myocardial T1 and ECV between LGE + and LGE- boys with DMD using a Wilcoxon rank-sum test. Results are reported as median and interquartile range (IQR). p-Values < 0.05 were considered significant. Receiver Operating Characteristic analysis was used to evaluate a binomial logistic classifier incorporating T1 mapping and LV function parameters in the tasks of distinguishing between healthy controls and boys with DMD, and detecting LGE status in DMD. The area under the curve is reported. RESULTS: Boys with DMD had significantly increased global native T1 [1332 (60) ms vs. 1289 (56) ms; p = 0.004] and increased within-slice standard deviation (SD) [100 (57) ms vs. 74 (27) ms; p = 0.001] compared to healthy controls. LGE- boys with DMD also demonstrated significantly increased lateral wall native T1 [1322 (68) ms vs. 1277 (58) ms; p = 0.001] compared to healthy controls. LGE + boys with DMD had decreased global myocardial post-contrast T1 [565 (113) ms vs 635 (126) ms; p = 0.04] and increased global myocardial ECV [32 (8) % vs. 28 (4) %; p = 0.02] compared to LGE- boys. In all classification tasks, T1-mapping biomarkers outperformed a conventional biomarker, LV ejection fraction. ECV was the best performing biomarker in the task of predicting LGE status (AUC = 0.95). CONCLUSIONS: Boys with DMD exhibit elevated native T1 compared to healthy, sex- and age-matched controls, even in the absence of LGE. Post-contrast T1 and ECV estimates from 3T CMR are also reported here for pediatric patients with DMD for the first time and can distinguish between LGE + from LGE- boys. In all classification tasks, T1-mapping biomarkers outperform a conventional biomarker, LVEF.

Altered brain diffusion tensor imaging indices in adolescents with the Fontan palliation.

PURPOSE: Single ventricle heart disease (SVHD) patients show injury in brain sites that regulate autonomic, mood, and cognitive functions. However, the nature (acute or chronic changes) and extent of brain injury in SVHD are unclear. Our aim was to examine regional brain tissue damage in SVHD over controls using DTI-based mean diffusivity (MD), axial diffusivity (AD), radial diffusivity (RD), and fractional anisotropy (FA) procedures. METHODS: We collected two DTI series (3.0-T MRI), mood and cognitive data, from 27 SVHD and 35 control adolescents. Whole-brain MD, AD, RD, and FA maps were calculated from each series, realigned and averaged, normalized to a common space, smoothed, and compared between groups using ANCOVA (covariates, age and sex; false discovery rate, p < 0.05). Region-of-interest analyses were performed to calculate MD, AD, RD, and FA values for magnitude assessment between groups. RESULTS: SVHD patients showed impaired mood and cognitive functions over healthy adolescents. Multiple brain sites in SVHD showed increased MD values, including the insula, caudate, cingulate, hypothalamus, thalamus, medial prefrontal and frontal cortices, parahippocampal gyrus, hippocampus, precentral gyrus, amygdala, cerebellum, corpus callosum, basal forebrain, mammillary bodies, internal capsule, midbrain, fornix, and occipital, parietal, and temporal cortices, indicating chronic tissue changes. Similar areas showed either increased AD or RD values, with RD changes more enhanced over AD in SVHD compared to controls. Few brain regions emerged with increased or decreased FA values in SVHD patients over controls. CONCLUSION: SVHD adolescents, more than a decade from their last surgical procedure, show widespread brain abnormalities in autonomic, mood, and cognitive regulatory areas. These findings indicate that brain injury is in a chronic stage in SVHD with predominantly myelin changes that may result from previous hypoxia/ischemia- or developmental-induced processes.

Home use of a compact, 12­lead ECG recording system for newborns.

BACKGROUND: An easy-to-operate ECG recorder should be useful for newborn screening for heart conditions, by health care workers - or parents. We developed a one-piece electrode strip and a compact, 12­lead ECG recorder for newborns. METHOD: We enrolled 2582 newborns in a trial to assess abilities of parents to record a 12­lead ECG on their infants (2-4 weeks-old). Newborns were randomized to recordings by parents (1290) or our staff (1292 controls). Educational backgrounds of parents varied, including 64% with no more than a high school diploma. RESULTS: For newborns randomized to parent recorded ECGs, 94% of parents completed a 10-minute recording. However, 42.6% asked for verbal help, and 12.7% needed physical help. ECG quality was the same for recordings by parents versus staff. CONCLUSIONS: By use of a one-piece electrode strip and a compact recorder, 87% of parents recorded diagnostic quality ECGs on their newborn infants, with minimal assistance.

Brain abnormalities in cognition, anxiety, and depression regulatory regions in adolescents with single ventricle heart disease.

BACKGROUND: Single ventricle heart disease (SVHD) adolescents show cognitive impairments and anxiety and depressive symptoms, indicating the possibility of brain injury in regions that control these functions. However, brain tissue integrity in cognition, anxiety, and depression regulatory sites in SVHD remains unclear. We examined brain tissue changes in SVHD compared to controls using T2-relaxometry procedures, which measure free water content and show tissue injury. METHODS: Proton-density and T2-weighted images, using a 3.0-Tesla MRI, as well as anxiety (Beck anxiety inventory [BAI]), depressive symptoms (patient health questionnaire-9 [PHQ-9]), and cognition (wide range assessment of memory and learning 2 [WRAML2] and Montreal cognitive assessment [MoCA]) data were collected from 20 SVHD (age: 15.8 ± 1.1 years, male/female: 11/9) and 36 controls (age: 16.0 ± 1.1 years, male/female: 19/17). Whole-brain T2-relaxation maps were calculated, normalized to a common space, smoothed, and compared between groups and sexes (analysis of covariance; covariates: age, sex; p < 0.001). RESULTS: SVHD subjects showed significantly increased BAI and PHQ-9 and reduced MoCA and WRAML2 scores over controls. Several brain regions in SVHD showed increased T2-relaxation values (chronic injury), including the cingulate, and insula, hippocampus/para-hippocampal gyrus, thalamus, hypothalamus, amygdala, frontal white matter, corpus callosum, brainstem, and cerebellar areas. Decreased T2-relaxation values (acute injury) emerged in a few regions, including the prefrontal and cerebellar cortices in SVHD over controls. In addition, male SVHD showed more brain changes over female SVHD. CONCLUSIONS: Adolescents with SVHD showed significant brain injury with variable male-female differences in areas that control cognition, anxiety, and depression, which may contribute to functional deficits found in the condition.

Left atrial function in children and young adult cancer survivors treated with anthracyclines.

BACKGROUND: The left atrium (LA) modulates left ventricular filling pressure and is a strong prognosticator in heart failure. Although anthracycline exposure may lead to impaired left ventricular (LV) function, the effects on LA function are not well-described in the younger population. We aim to evaluate LA function in children exposed to anthracyclines. METHODS: Children exposed to anthracyclines with pre- and post-treatment echocardiographic imaging were enrolled. Measures of LA function (LA ejection fraction [LA EF], global longitudinal strain [GLS], and peak GLS rate) were quantified using 2D speckle tracking echocardiography pre- and post-anthracycline therapy and were compared. Segments with poor tracking were excluded. RESULTS: Fifty-five children (age 13 [SD 5] years) treated with anthracyclines were evaluated. LA EF, GLS, and peak GLS rate were lower after anthracycline exposure. Mean changes were as follows: LA EF (pre-73.5 [SD 7.7]% vs post-70.6 [SD 8.2]%, P = 0.06), GLS (-34.2 [SD 8.4]% vs -31.9 [SD 7.1]%, P = 0.09), peak GLS rate (2.2 [SD 0.8] s-1 vs 2.0 [SD 0.6] s-1 , P = 0.18). When stratified by pre- (≤12 years old) vs post-puberty (>12 years old), prepubescent patients (n = 21) had statistically significant changes in pre/post LA GLS (P = 0.01) and LA EF (P = 0.01). In models adjusted for radiation dose, age, gender, body surface area, or cumulative anthracycline dose, there were no significant relationships in the absolute difference between pre/post LA EF (P = 0.34) or LA GLS (P = 0.18). CONCLUSIONS: In children exposed to anthracyclines, short-term effects on LA function were minimal in those with preserved LV EF. Age-dependent LA susceptibility to anthracycline requires further study.

Design for the sacubitril/valsartan (LCZ696) compared with enalapril study of pediatric patients with heart failure due to systemic left ventricle systolic dysfunction (PANORAMA-HF study).

BACKGROUND: Sacubitril/valsartan (LCZ696) is an angiotensin receptor neprilysin inhibitor approved for the treatment of adult heart failure (HF); however, the benefit of sacubitril/valsartan in pediatric HF patients is unknown. STUDY DESIGN: This global multi-center study will use an adaptive, seamless two-part design. Part 1 will assess the pharmacokinetics/pharmacodynamics of single ascending doses of sacubitril/valsartan in pediatric (1 month to <18 years) HF patients with systemic left ventricle and reduced left ventricular systolic function stratified into 3 age groups (Group 1: 6 to <18 years; Group 2: 1 to <6 years; Group 3: 1 month to <1 year). Part 2 is a 52-week, efficacy and safety study where 360 eligible patients will be randomized to sacubitril/valsartan or enalapril. A novel global rank primary endpoint derived by ranking patients (worst-to-best outcome) based on clinical events such as death, initiation of mechanical life support, listing for urgent heart transplant, worsening HF, measures of functional capacity (NYHA/Ross scores), and patient-reported HF symptoms will be used to assess efficacy. CONCLUSION: The PANORAMA-HF study, which will be the largest prospective pediatric HF trial conducted to date and the first to use a global rank primary endpoint, will determine whether sacubitril/valsartan is superior to enalapril for treatment of pediatric HF patients with reduced systemic left ventricular systolic function.

Effect of free-breathing on left ventricular rotational mechanics in healthy subjects and patients with duchenne muscular dystrophy.

PURPOSE: Cardiovascular magnetic resonance imaging exams can be performed during free-breathing. This may be especially important for boys with Duchenne muscular dystrophy (DMD) given their frequently limited breath-hold abilities. The impact of the respiratory compensation method on quantitative measurements of left ventricular (LV) rotational mechanics is incompletely understood. The purpose of this study was to evaluate differences in LV rotational mechanics acquired during breath-holding (BH), free-breathing with averaging (AVG), and free-breathing with respiratory bellows gating (BEL). METHODS: LV short-axis tagged images from healthy subjects (N = 16) and DMD patients (N = 5) were acquired with BH, AVG, and BEL. LV twist and circumferential-longitudinal shear (CL-shear) angle were measured using the Fourier Analysis of STimulated echoes (FAST) method. RESULTS: Peak LV twist estimates using BEL were significantly lower compared with BH in both healthy subjects (10.2 ± 3.6 ° versus 12.9 ± 2.3 °, P = 0.003) and patients with DMD (8.6 ± 3.6 ° versus 10.5 ± 3.6 °, P = 0.004). AVG results were in between BEL and BH. No significant differences in CL-shear were detected between BEL and BH. CONCLUSION: Breath-holding directly affects estimates of peak LV twist, but not CL-shear. Using a free-breathing strategy for the evaluation of cardiac function is important for intrasubject longitudinal studies, intersubject comparisons, and multicenter trials for patients with DMD. Magn Reson Med 77:864-869, 2017. © 2016 International Society for Magnetic Resonance in Medicine.

Long-term outcomes of simultaneous heart and kidney transplantation in pediatric recipients.

Pediatric sHKTx has become an effective therapy for patients with combined cardiac and renal failure. Often, these patients develop human leukocyte antigen antibodies from their previous allografts and are therefore more difficult to re-transplant. We describe the largest case series of a predominantly sensitized pediatric sHKTx with emphasis on medical management and patient outcomes. Demographics, clinical characteristics, antibody, and biopsy data were retrospectively collected from University of California, Los Angeles database and correlated with short- and long-term patient and allograft outcomes of all sHKTx performed between 2002 and 2015. We identified seven pediatric patients who underwent sHKTx at our center. Mean age at time of sHKTx was 13.7 years and 85.7% were re-graft patients. 57.1% were sensitized with cPRA >50% and another 57.1% had preformed donor-specific antibody. Five-year renal allograft survival and patient survival was 85.7% for both end-points. The remaining six patients are all alive (mean follow-up 78.5 months) with good kidney and heart function. sHKTx in a population with increased immunological risk can be associated with good long-term outcomes and offers potential guidance to the pediatric transplant community where data are limited.

Free-breathing variable flip angle balanced SSFP cardiac cine imaging with reduced SAR at 3T.

PURPOSE: To develop a free-breathing variable flip angle (VFA) balanced steady-state free precession (bSSFP) cardiac cine imaging technique with reduced specific absorption rate (SAR) at 3 Tesla. METHODS: Free-breathing VFA (FB-VFA) images in the short-axis and four-chamber views were acquired using an optimal VFA scheme, then compared with conventional breath-hold constant flip angle (BH-CFA) acquisitions. Two cardiac MRI experts used a 5-point scale to score images from healthy subjects (N = 10). The left ventricular ejection fraction, end diastolic volume (LVEDV), end systolic volume, stroke volume (LVSV), and end diastolic myocardial mass (LVEDM) were determined by manual contour analysis for BH-CFA and FB-VFA. A pilot evaluation of FB-VFA was performed in one patient with Duchenne muscular dystrophy. RESULTS: FB-VFA SAR was 25% lower than BH-CFA with similar blood-myocardium contrast. The qualitative FB-VFA score was lower than the BH-CFA for the short-axis (3.1 ± 0.5 versus 4.3 ± 0.8; P < 0.05) and the four-chamber view (3.4 ± 0.4 versus 4.6 ± 0.6; P < 0.05). The LVEDV and the LVSV were 5% and 12% larger (P < 0.05) for FB-VFA compared with BH-CFA. There was no difference in LVEDM. CONCLUSION: FB-VFA bSSFP cardiac cine imaging decreased the SAR at 3T with image quality sufficient to perform cardiac functional analysis. Magn Reson Med 76:1210-1216, 2016. © 2015 Wiley Periodicals, Inc.

Exercise Training in Cancer Survivors.

Numerous observational reports suggesting the positive benefits of physical activity in patients diagnosed with cancer have prompted multiple investigative studies involving exercise training for patients throughout the continuum of a cancer diagnosis. Physicians and primary caregivers struggle to find clearly defined guidelines or recommendations for exercise prescriptions that are specific to their widely variable cancer patient populations. Although there continues to be emerging evidence supporting physical activity in cancer survivors, further research is required to investigate new and existing outcomes, methods to sustain positive effects of exercise over time, and to better define guidelines for exercise interventions that include exercise type, frequency, intensity, duration, and timing. Studies of exercise interventions on patients with a range of cancer diagnoses and differing cancer treatments, and involving the pediatric population should be further investigated to document benefit and develop more refined recommendations for physical activity in all cancer survivors.

Compromised Cerebral Arterial Perfusion, Altered Brain Tissue Integrity, and Cognitive Impairment in Adolescents with Complex Congenital Heart Disease.

(1) Introduction: Adolescents with complex congenital heart disease (CCHD) show brain tissue injuries in regions associated with cognitive deficits. Alteration in cerebral arterial perfusion (CAP), as measured by arterial transit time (ATT), may lead to perfusion deficits and potential injury. Our study aims to compare ATT values between CCHD patients and controls and assess the associations between ATT values, MD values, and cognitive scores in adolescents with CCHD. (2) Methods: 37 CCHD subjects, 14-18 years of age, who had undergone surgical palliation and 30 healthy controls completed cognitive testing and brain MRI assessments using a 3.0-Tesla scanner. ATT values and regional brain mean diffusivity [MD] were assessed for the whole brain using diffusion tensor imaging. (3) Results: The mean MoCA values [23.1 ± 4.1 vs. 28.1 ± 2.3; p < 0.001] and General Memory Index, with a subscore of WRAML2 [86.8 ± 15.4 vs. 110.3 ± 14.5; p < 0.001], showed significant cognitive deficits in CCHD patients compared to controls. The mean global ATT was significantly higher in CCHD patients versus controls (mean ± SD, s, 1.26 ± 0.11 vs. 1.19 ± 0.11, p = 0.03), respectively. The partial correlations between ATT values, MD values, and cognitive scores (p < 0.005) showed significant associations in areas including the hippocampus, prefrontal cortices, cerebellum, caudate, anterior and mid cingulate, insula, thalamus, and lingual gyrus. (4) Conclusions: Adolescents with CCHD had prolonged ATTs and showed correlation with clinical measurements of cognitive impairment and MRI measurements of brain tissue integrity. This suggests that altered CAP may play a role in brain tissue injury and cognitive impairment after surgical palliation.

Uncertain benefit of statins in pediatric heart transplant recipients: A PHTS analysis.

BACKGROUND: Cardiac allograft vasculopathy (CAV) is a leading cause of graft failure in pediatric heart transplant recipients (HTRs). Early statin use has been shown to reduce CAV incidence and all-cause mortality in adult HTRs. We sought to evaluate the contemporary prevalence and trends of statin use in pediatric HTRs and the association between statin use with CAV development and graft failure. METHODS: Patients aged <17 years at the time of primary heart transplant who survived to ≥3 years without CAV were identified from the Pediatric Heart Transplant Society database (2001-2018). Statin use in the first 3 years posttransplant was defined as consecutive, intermediate, or absent. Kaplan-Meier survival, multivariable modeling, and propensity score-matched analyses evaluated associations between statin use and CAV incidence and graft survival, with subanalyses performed on subjects aged ≥10 years at transplant. RESULTS: Among 3,485 (of which 1,086 aged ≥10 years) HTRs, 584 (17%) received consecutive statin therapy, 647 (19%) received intermediate use, and 2,254 (65%) received no statin therapy. Statin use varied widely between sites, with increasing use in the ≥10-year-old cohort over time. By multivariate analysis, statin use was not associated with graft loss. Consecutive statin use was also not associated with graft survival or freedom from CAV development when compared to absent statin use in unmatched or propensity-matched analyses. CONCLUSIONS: While statins remain commonly utilized in pediatric HTRs, early consecutive statin therapy did not decrease CAV incidence or graft loss. The differing effects of statins on CAV development and progression in pediatric vs adult HTRs suggest differing risk and mediating factors and require further study.

Whole-Exome Sequencing Identifies Homozygote Nonsense Variants in LMOD2 Gene Causing Infantile Dilated Cardiomyopathy.

As an essential component of the sarcomere, actin thin filament stems from the Z-disk extend toward the middle of the sarcomere and overlaps with myosin thick filaments. Elongation of the cardiac thin filament is essential for normal sarcomere maturation and heart function. This process is regulated by the actin-binding proteins Leiomodins (LMODs), among which LMOD2 has recently been identified as a key regulator of thin filament elongation to reach a mature length. Few reports have implicated homozygous loss of function variants of LMOD2 in neonatal dilated cardiomyopathy (DCM) associated with thin filament shortening. We present the fifth case of DCM due to biallelic variants in the LMOD2 gene and the second case with the c.1193G>A (p.W398*) nonsense variant identified by whole-exome sequencing. The proband is a 4-month male infant of Hispanic descent with advanced heart failure. Consistent with previous reports, a myocardial biopsy exhibited remarkably short thin filaments. However, compared to other cases of identical or similar biallelic variants, the patient presented here has an unusually late onset of cardiomyopathy during infancy. Herein, we present the phenotypic and histological features of this variant, confirm the pathogenic impact on protein expression and sarcomere structure, and discuss the current knowledge of LMOD2-related cardiomyopathy.