Showing papers by "Jane W. Newburger published in 2015"

De novo mutations in congenital heart disease with neurodevelopmental and other congenital anomalies.

Abstract: Congenital heart disease (CHD) patients have an increased prevalence of extracardiac congenital anomalies (CAs) and risk of neurodevelopmental disabilities (NDDs). Exome sequencing of 1213 CHD parent-offspring trios identified an excess of protein-damaging de novo mutations, especially in genes highly expressed in the developing heart and brain. These mutations accounted for 20% of patients with CHD, NDD, and CA but only 2% of patients with isolated CHD. Mutations altered genes involved in morphogenesis, chromatin modification, and transcriptional regulation, including multiple mutations in RBFOX2, a regulator of mRNA splicing. Genes mutated in other cohorts examined for NDD were enriched in CHD cases, particularly those with coexisting NDD. These findings reveal shared genetic contributions to CHD, NDD, and CA and provide opportunities for improved prognostic assessment and early therapeutic intervention in CHD patients.

Neurodevelopmental outcomes after cardiac surgery in infancy.

Abstract: BACKGROUND: Neurodevelopmental disability is the most common complication for survivors of surgery for congenital heart disease (CHD). METHODS: We analyzed individual participant data from studies of children evaluated with the Bayley Scales of Infant Development, second edition, after cardiac surgery between 1996 and 2009. The primary outcome was Psychomotor Development Index (PDI), and the secondary outcome was Mental Development Index (MDI). RESULTS: Among 1770 subjects from 22 institutions, assessed at age 14.5 ± 3.7 months, PDIs and MDIs (77.6 ± 18.8 and 88.2 ± 16.7, respectively) were lower than normative means (each P P ≤ .01). After adjustment for these factors, PDIs improved over time (0.39 points/year, 95% confidence interval 0.01 to 0.78; P = .045). Risk factors for lower MDI were lower birth weight, male gender, less maternal education, and presence of a genetic/extracardiac anomaly (all P P = .02). CONCLUSIONS: Early neurodevelopmental outcomes for survivors of cardiac surgery in infancy have improved modestly over time, but only after adjustment for innate patient risk factors. As more high-risk CHD infants undergo cardiac surgery and survive, a growing population will require significant societal resources.

Executive Function in Children and Adolescents with Critical Cyanotic Congenital Heart Disease

Abstract: Children and adolescents with critical cyanotic congenital heart disease (CHD) are at risk for deficits in aspects of executive function (EF). The primary aim of this investigation was to compare EF outcomes in three groups of children/adolescents with severe CHD and controls (ages 10-19 years). Participants included 463 children/adolescents with CHD [dextro-transposition of the great arteries (TGA), n=139; tetralogy of Fallot (TOF), n=68; and, single-ventricle anatomy requiring Fontan procedure (SVF), n=145] and 111 controls, who underwent laboratory and informant-based evaluation of EF skills. Rates of EF impairment on D-KEFS measures were nearly twice as high for CHD groups (75-81%) than controls (43%). Distinct EF profiles were documented between CHD groups on D-KEFS tasks. Deficits in flexibility/problem-solving and verbally mediated EF skills were documented in all three CHD groups; visuo-spatially mediated EF abilities were impaired in TOF and SVF groups, but preserved in TGA. Parent, teacher, and self-report ratings on the BRIEF highlighted unique patterns of metacognitive and self-regulatory concerns across informants. CHD poses a serious threat to EF development. Greater severity of CHD is associated with worse EF outcomes. With increased understanding of the cognitive and self-regulatory vulnerabilities experienced by children and adolescents with CHD, it may be possible to identify risks early and provide individualized supports to promote optimal neurodevelopment.

Neuropsychological Status and Structural Brain Imaging in Adolescents With Single Ventricle Who Underwent the Fontan Procedure.

Abstract: Background Few studies have described the neuropsychological outcomes and frequency of structural brain or genetic abnormalities in adolescents with single ventricle who underwent the Fontan procedure. Methods and Results In a cross‐sectional, single‐center study, we enrolled 156 subjects with single ventricle, mean age 14.5±2.9 years, who had undergone the Fontan procedure. Scores in the entire cohort on a standard battery of neuropsychological tests were compared with those of normative populations or to those of a group of 111 locally recruited healthy adolescents. They also underwent brain magnetic resonance imaging and were evaluated by a clinical geneticist. Genetic abnormalities were definite in 16 subjects (10%) and possible in 49 subjects (31%). Mean Full‐Scale IQ was 91.6±16.8, mean Reading Composite score was 91.9±17.2, and mean Mathematics Composite score was 92.0±22.9, each significantly lower than the population means of 100±15. Mean scores on other neuropsychological tests were similarly lower than population norms. In multivariable models, risk factors for worse neuropsychological outcomes were longer total support and circulatory arrest duration at first operation, presence of a genetic abnormality, more operations and operative complications, more catheterization complications, and seizure history. The frequency of any abnormality on magnetic resonance imaging was 11 times higher among Fontan adolescents than referents (66% versus 6%); 19 (13%) patients had evidence of a stroke, previously undiagnosed in 7 patients (40%). Conclusions The neuropsychological deficits and high frequencies of structural brain abnormalities in adolescents who underwent the Fontan procedure highlight the need for research on interventions to improve the long‐term outcomes in this high‐risk group.

Adolescents with tetralogy of Fallot: neuropsychological assessment and structural brain imaging.

Abstract: Background Few data are available on the neuropsychological, behavioural, or structural brain imaging outcomes in adolescents who underwent corrective surgery in infancy for tetralogy of Fallot. Methods In this single-centre cross-sectional study, we enrolled 91 adolescents (13-16 years old) with tetralogy of Fallot and 87 referent subjects. Assessments included tests of academic achievement, memory, executive functions, visual-spatial skills, attention, and social cognition, as well as brain magnetic resonance imaging. Results Genetic abnormalities or syndromes were present in 25% of tetralogy of Fallot patients, who had markedly greater neuropsychological morbidities than did patients without a syndrome. However, even patients without a syndrome performed significantly worse than the referent group or population norms in all of the neuropsychological domains assessed. In multivariable regression in those without a genetic/phenotypic syndrome, the strongest predictors of adverse late neurodevelopmental outcomes included a greater number of complications at the first operation, more total surgical complications across all operations, and occurrence of post-operative seizures. The presence of at least one abnormality on structural magnetic resonance imaging was more frequent in tetralogy of Fallot patients than the referent group (42% versus 8%). Conclusions Adolescents with tetralogy of Fallot are at increased neurodevelopmental risk and would benefit from ongoing surveillance and educational supports even after childhood.

Perioperative cerebral hemodynamics and oxygen metabolism in neonates with single-ventricle physiology.

Abstract: Congenital heart disease (CHD) patients are at risk for neurodevelopmental delay. The etiology of these delays is unclear, but abnormal prenatal cerebral maturation and postoperative hemodynamic instability likely play a role. A better understanding of these factors is needed to improve neurodevelopmental outcome. In this study, we used bedside frequency-domain near infrared spectroscopy (FDNIRS) and diffuse correlation spectroscopy (DCS) to assess cerebral hemodynamics and oxygen metabolism in neonates with single-ventricle (SV) CHD undergoing surgery and compared them to controls. Our goals were 1) to compare cerebral hemodynamics between unanesthetized SV and healthy neonates, and 2) to determine if FDNIRS-DCS could detect alterations in cerebral hemodynamics beyond cerebral hemoglobin oxygen saturation (SO2). Eleven SV neonates were recruited and compared to 13 controls. Preoperatively, SV patients showed decreased cerebral blood flow (CBFi), cerebral oxygen metabolism (CMRO2i) and SO2; and increased oxygen extraction fraction (OEF) compared to controls. Compared to preoperative values, unstable postoperative SV patients had decreased CMRO2i and CBFi, which returned to baseline when stable. However, SO2 showed no difference between unstable and stable states. Preoperative SV neonates are flow-limited and show signs of impaired cerebral development compared to controls. FDNIRS-DCS shows potential to improve assessment of cerebral development and postoperative hemodynamics compared to SO2 alone.

Acquisition, Analysis, and Sharing of Data in 2015 and Beyond: A Survey of the Landscape A Conference Report From the American Heart Association Data Summit 2015

Abstract: Background A 1.5‐day interactive forum was convened to discuss critical issues in the acquisition, analysis, and sharing of data in the field of cardiovascular and stroke science. The discussion will serve as the foundation for the American Heart Association's (AHA's) near‐term and future strategies in the Big Data area. The concepts evolving from this forum may also inform other fields of medicine and science. Methods and Results A total of 47 participants representing stakeholders from 7 domains (patients, basic scientists, clinical investigators, population researchers, clinicians and healthcare system administrators, industry, and regulatory authorities) participated in the conference. Presentation topics included updates on data as viewed from conventional medical and nonmedical sources, building and using Big Data repositories, articulation of the goals of data sharing, and principles of responsible data sharing. Facilitated breakout sessions were conducted to examine what each of the 7 stakeholder domains wants from Big Data under ideal circumstances and the possible roles that the AHA might play in meeting their needs. Important areas that are high priorities for further study regarding Big Data include a description of the methodology of how to acquire and analyze findings, validation of the veracity of discoveries from such research, and integration into investigative and clinical care aspects of future cardiovascular and stroke medicine. Potential roles that the AHA might consider include facilitating a standards discussion (eg, tools, methodology, and appropriate data use), providing education (eg, healthcare providers, patients, investigators), and helping build an interoperable digital ecosystem in cardiovascular and stroke science. Conclusion There was a consensus across stakeholder domains that Big Data holds great promise for revolutionizing the way cardiovascular and stroke research is conducted and clinical care is delivered; however, there is a clear need for the creation of a vision of how to use it to achieve the desired goals. Potential roles for the AHA center around facilitating a discussion of standards, providing education, and helping establish a cardiovascular digital ecosystem. This ecosystem should be interoperable and needs to interface with the rapidly growing digital object environment of the modern‐day healthcare system.

Left Ventricular Strain and Myocardial Fibrosis in Congenital Aortic Stenosis.

Abstract: The aim of this study was to evaluate whether left ventricular (LV) systolic strain in children and young adults with congenital aortic stenosis (AS) and preserved ejection fraction was different from normal subjects and to determine whether any alterations in strain were related to myocardial fibrosis. In this retrospective study, 29 patients with congenital AS with a median age of 15.3 years (range 1.7 to 23.7), highest lifetime AS peak Doppler gradient of 73 mm Hg (22 to 110), most recent AS peak Doppler gradient of 49 mm Hg (0 to 90), and ejection fraction of 65 (55 to 79) were included. Strain was measured using 2-dimensional speckle-tracking echocardiography. Cardiac magnetic resonance was used to identify focal fibrosis by late gadolinium enhancement (LGE) and diffuse fibrosis by calculating the extracellular volume fraction (ECV) from T1 measurements. Compared to age-matched controls (n = 29), patients with AS had reduced LV longitudinal (17.0 ± 3.0% vs 20.6 ± 2.2%, p

Carotid artery intima-media thickness measurements in the youth: reproducibility and technical considerations.

Abstract: Background Carotid artery intima-media thickness (CIMT), a marker of atherosclerosis, is increased in youth at risk for future cardiovascular disease. Some pediatric studies have used CIMT as a primary outcome in clinical trials, yet data are limited on the standardization of methodology in children. The goal of this study was to evaluate reproducibility of CIMT measurements using two different measurement techniques. Methods Carotid artery ultrasound studies of children and adolescents obtained as a component of a research study in Kawasaki syndrome were retrospectively analyzed. The CIMTs of both common carotid arteries (CCAs) were measured by one of two sonographers at the time in the cardiac cycle when resolution subjectively was determined to be optimal (Opt-CIMT). These sonographers blindly remeasured a random sample of studies of their own and each other's, using the same method. Another observer made CIMT measurements using exclusively frames on the R wave (R-CIMT). A fourth observer independently measured a random sample of studies twice with the R-CIMT method. Results Carotid artery images from 184 subjects (mean age, 14.7 ± 2.2 years) were analyzed. The intraclass correlation coefficient for interobserver variability was 0.86 (95% confidence interval [CI], 0.69–0.94) compared with 0.85 (95% CI, 0.65–0.93) for the right and 0.86 (95% CI, 0.67–0.94) versus 0.95 (95% CI, 0.87–0.98) for the left CCA for Opt-CIMT and R-CIMT, respectively. R-CIMT was significantly thicker than Opt-CIMT (right CCA, 0.439 ± 0.030 vs 0.428 ± 0.024 mm, P P Conclusion Pediatric CIMT measurements have excellent reproducibility when the same methodology is applied but vary significantly throughout the cardiac cycle. This report highlights the need to standardize CIMT measurements in the youth and supports the use of electrocardiographic timing, as recommended in adults, in pediatric longitudinal studies.

Management of Kawasaki disease in resource-limited settings.

Abstract: GLOBAL EPIDEMIOLOGY Kawasaki disease (KD) is a vasculitis of unknown etiology that predominantly affects infants and young children. The incidence of KD is increasing in many countries. Japan currently has an incidence of 234/100,000 children <5 years of age (corresponding to approximately 1 in 150 Japanese children having KD by age 10 years). The incidence is 134/100,000 in Korea and 69/100,000 in Taiwan. The incidence in the Europe and Australia is approximately 6–9/100,000 and in the US 9–20/100,000. KD is increasingly reported from all regions of the world, particularly those undergoing rapid industrialization. There are few epidemiological data from resource-limited settings. Anecdotal evidence from India suggests that KD may overtake acute rheumatic fever as the commonest cause of pediatric acquired heart disease. In Chandigarh, North India, the hospital-based incidence of KD is 4.5/100,000 children <15 years of age, although this is probably an underestimate. It is important to recognize that KD is not limited to resource-rich countries; awareness of the features of KD and the possibility of the diagnosis in any young child with unexplained prolonged fever is relevant to all settings and populations. If KD is undiagnosed and untreated, the coronary artery complications, which may occur in up to 25%, are likely to contribute substantially to the increasing burden of cardiovascular disease in adults in the coming decades. Predictive models using US and Taiwanese epidemiologic data suggest that a large and growing patient population will require ongoing management of coronary artery disease following KD. The rising number of KD patients with coronary aneurysms may also pose a significant burden on health resources in resource-limited settings.

Associations Between Day of Admission and Day of Surgery on Outcome and Resource Utilization in Infants With Hypoplastic Left Heart Syndrome Who Underwent Stage I Palliation (from the Single Ventricle Reconstruction Trial)

Abstract: Newborns with hypoplastic left heart syndrome and other single right ventricular variants require substantial health care resources. Weekend acute care has been associated with worse outcomes and increased resource use in other populations but has not been studied in patients with single ventricle. Subjects of the Single Ventricle Reconstruction trial were classified by whether they had a weekend admission and by day of the week of Norwood procedure. The primary outcome was hospital length of stay (LOS); secondary outcomes included transplant-free survival, intensive care unit (ICU) LOS, and days of mechanical ventilation. The Student's t test with log transformation and the Wilcoxon rank-sum test were used to analyze associations. Admission day was categorized for 533 of 549 subjects (13% weekend). The day of the Norwood was Thursday/Friday in 39%. There was no difference in median hospital LOS, transplant-free survival, ICU LOS, or days ventilated for weekend versus non-weekend admissions. Day of the Norwood procedure was not associated with a difference in hospital LOS, transplant-free survival, ICU LOS, or days ventilated. Prenatally diagnosed infants born on the weekend had lower mean birth weight, younger gestational age, and were more likely to be intubated but did not have a difference in measured outcomes. In conclusion, in this cohort of patients with single right ventricle, neither weekend admission nor end-of-the-week Norwood procedure was associated with increased use of hospital resources or poorer outcomes. We speculate that the complex postoperative course following the Norwood procedure outweighs any impact that day of admission or operation may have on these outcomes.

Differentiating standardized clinical assessment and management plans from clinical practice guidelines.

Abstract: Academic Medicine, Vol. 90, No. 8 / August 2015 1002 have been well designed, although with six years and 50,000 patients’ worth of experience, we are getting better) will result in persuasive data that not only promote rapid improvement in care but also generate excitement among frontline clinicians eager to learn more. This excitement is a fundamental requirement if we are to change our health care system for the better.

A5.2 Kawasaki disease and exposure to fine particulate air pollution

Abstract: Introduction Environmental factors play a pathogenic role in the aetiology of Kawasaki Disease (KD). Fine particulate matter (aerodynamic diameter less than or equal to a 2.5-mm cut point, PM 2.5 ) is a measurable component of ambient urban pollution. Environmental influences associated with weather, spatial location, and temporal season have been shown to contribute, however the short term environmental triggers which contribute to the clinically recognised onset event of KD remain unclear. Potentially, short-term pollution exposures act as covariates to clinical disease presentation and outcome, including measures of coronary artery involvement. Methods A case-crossover study design was used to analyse associations of short-term PM 2.5 exposures with the event date of KD symptom onset (fever) from cases residing in the metropolitan regions of Boston, Toronto, Cleveland, Chicago, San Diego, Denver, and Salt Lake City. Time trends, seasonality, month, and weekday were controlled for by matching. Selected exposure windows (up to 14 days) of PM 2.5 . were examined. Results We have assembled PM 2.5 exposure measurements from urban monitors and have carefully imputed PM 2.5 to provide day-to-day temporal variability and resolution for reliable time series indexes of pollution exposures for each metropolitan area. 3,009 KD events were included where the subject resided within one of the study metro areas and the onset of disease occurred during the years with available PM 2.5 monitoring. The estimated relative risks (and 95% CI’s) of an onset event of KD associated with a 10 µg/m 3 PM 2.5 lagged moving average concentration of lagged exposure period (concurrent day and preceding day (s)) revealed no evidence of a consistent, statistically significant, positive association between elevated exposure to PM 2.5 and elevated risk of KD onset. Extended analysis with stratification by city, sex, and age did not provide evidence of a consistent, statistically significant, positive association between elevated exposure to PM 2.5 and elevated risk of KD onset for any of the strata. Conclusions Well-constructed, environmental epidemiology studies examining the triggers of disease onset and exacerbation in paediatric rheumatic diseases are few and far between. While our results failed to establish a risk of the event of KD fever onset with short-term ambient particulate pollution exposure, negative findings from this study add to the growing field of particulate induced environmental epidemiology research of Kawasaki Disease.