Associations of Congenital Heart Disease with Deprivation Index by Rural-Urban Maternal Residence: A Population-Based Retrospective Cohort Study in Ontario, Canada.

Background The risk of congenital heart disease (CHD) has been found to vary by maternal socioeconomic status (SES) and rural-urban residence. In this study, we examined associations of CHD with two maternal SES indicators and maternal rural-urban residence. Approach This was a population-based retrospective cohort study, including singleton stillbirths and live hospital births from April 1, 2012 to March 31, 2018 in Ontario, Canada. We linked the BORN data and Canadian Institute for Health Information databases. Multivariable logistic regression models were used to examine associations of CHD with material deprivation index (MDI), social deprivation index (SDI), and maternal residence while adjusting for maternal age at birth, parity, assisted reproductive technology, obesity, previous caesarean section, pre-existing health conditions, substance use during pregnancy, and infant’s sex. MDI and SDI were estimated at a dissemination area level and categorized into quintiles (Q1-Q5). Results This cohort included 798,173 singletons. In maternal urban residence, the p trend (Cochran–Armitage test) was < 0.0001 for both MDI and SDI; while for rural residence, it was 0.002 and 0.98, respectively. Infants living in the most materially deprived neighbourhoods (Q5) was associated with higher odd of CHD (aOR: 1.21, 95% CI: 1.12-1.29) compared to Q1. Similarly, infants living in the most socially deprived neighbourhoods (SDI Q5) had 18% increase in the odds of CHD (aOR: 1.18, 95% CI: 1.1-1.26) compared to Q1. Rural infants had 13% increase in the odds of CHD compared to their urban counterparts. After stratifying by maternal rural-urban residence, we still detected higher odds of CHD with two indices in urban residence but only MDI in rural residence. Conclusion Higher material and social deprivation and rural residence were associated with higher odds of CHD. Health interventions and policies should reinforce the need for optimal care for all families, particularly underprivileged families in both rural and urban regions

Machine Learning Identifies Clinical and Genetic Factors Associated With Anthracycline Cardiotoxicity in Pediatric Cancer Survivors

BACKGROUND Despite known clinical risk factors, predicting anthracycline cardiotoxicity remains challenging. OBJECTIVES This study sought to develop a clinical and genetic risk prediction model for anthracycline cardiotoxicity in childhood cancer survivors. METHODS We performed exome sequencing in 289 childhood cancer survivors at least 3 years from anthracycline exposure. In a nested case-control design, 183 case patients with reduced left ventricular ejection fraction despite low-dose doxorubicin (\u3c= 250 mg/m(2)), and 106 control patients with preserved left ventricular ejection fraction despite doxorubicin \u3e250 mg/m(2) were selected as extreme phenotypes. Rare/low-frequency variants were collapsed to identify genes differentially enriched for variants between case patients and control patients. The expression levels of 5 top-ranked genes were evaluated in human induced pluripotent stem cell-derived cardiomyocytes, and variant enrichment was confirmed in a replication cohort. Using random forest, a risk prediction model that included genetic and clinical predictors was developed. RESULTS Thirty-one genes were differentially enriched for variants between case patients and control patients (p \u3c 0.001). Only 42.6% case patients harbored a variant in these genes compared to 89.6% control patients (odds ratio: 0.09; 95% confidence interval: 0.04 to 0.17; p = 3.98 x 10(-15)). A risk prediction model for cardiotoxicity that included clinical and genetic factors had a higher prediction accuracy and lower misclassification rate compared to the clinical-only model. In vitro inhibition of gene-associated pathways (PI3KR2, ZNF827) provided protection from cardiotoxicity in cardiomyocytes. CONCLUSIONS Our study identified variants in cardiac injury pathway genes that protect against cardiotoxicity and informed the development of a prediction model for delayed anthracycline cardiotoxicity, and it also provided new targets in autophagy genes for the development of cardio-protective drugs

Impacting Children’s Physical and Mental Health through Kinesiology Support in Clinical Care: A Randomized Controlled Trial Protocol

Objectives To enhance the confidence of children and adolescents with medical conditions and disabilities to engage in healthy, active lifestyles. Children with medical conditions and disabilities often exhibit more sedentary lifestyles relative to peers and are at increased risk of poor health outcomes. Clinical experience suggests physical activity confidence is an important factor influencing physical activity participation. Methods This randomized controlled trial evaluates an evidence-based intervention targeting physical activity confidence among children and adolescents with medical conditions and disabilities. Potential participants, 8 to 18 years of age diagnosed with a medical condition or disability, will be screened for adequate physical activity motivation but a lack confidence. Consenting participants (n=128) will be randomized 1:1 to a 12-week in-person or virtual physical activity intervention (24 hours/week total) led by a Registered Kinesiologist or control (assessments only). The intervention will combine physical activity participation with education about physical activity knowledge, goal setting, motivation and self-management. Primary outcomes are self-reported physical activity confidence and motivation at baseline, post-intervention and three months following intervention completion. A secondary outcome will be daily physical activity minutes assessed by accelerometry. A repeated measures mixed model will be used to compare outcomes between the in-person intervention, virtual intervention, and control groups (alpha=0.05). Conclusions This trial aims to assess the impact of a novel application of behaviour change theory on physical activity confidence among children and adolescents living with medical conditions or disabilities. Increased physical activity confidence, knowledge and skills could enable these youth to lead a more active lifestyle

Exome Sequencing Identifies Rare Variants in Multiple Genes in Atrioventricular Septal Defect

Purpose The genetic etiology of atrioventricular septal defect (AVSD) is unknown in 40% cases. Conventional sequencing and arrays have identified the etiology in only a minority of non-syndromic individuals with AVSD. Methods: Whole exome sequencing was performed in 81 unrelated probands with AVSD to identify potentially causal variants in a comprehensive set of 112 genes with strong biological relevance to AVSD. Results: A significant enrichment of rare and rare/damaging variants was identified in the gene set, compared with controls (odds ratio 1.52, 95% confidence interval 1.35–1.71, p = 4.8 x 10-11). The enrichment was specific to AVSD probands compared with a non-AVSD cohort with tetralogy of Fallot (odds ratio 2.25, 95% confidence interval 1.84-2.76, p = 2.2 x 10-16). Six genes (NIPBL, CHD7, CEP152, BMPR1a, ZFPM2 and MDM4) were enriched for rare variants in AVSD compared to controls, including three syndrome-associated genes (NIPBL, CHD7, CEP152). The findings were confirmed in a replication cohort of 81 AVSD probands. Conclusion: Mutations in genes with strong biological relevance to AVSD, including syndrome-associated genes, can contribute to AVSD even in those with isolated heart disease. The identification of a gene set associated with AVSD will facilitate targeted genetic screening in this cohort

Common Genetic Variants Contribute to Risk of Transposition of the Great Arteries.

RATIONALE: Dextro-transposition of the great arteries (D-TGA) is a severe congenital heart defect which affects approximately 1 in 4,000 live births. While there are several reports of D-TGA patients with rare variants in individual genes, the majority of D-TGA cases remain genetically elusive. Familial recurrence patterns and the observation that most cases with D-TGA are sporadic suggest a polygenic inheritance for the disorder, yet this remains unexplored. OBJECTIVE: We sought to study the role of common single nucleotide polymorphisms (SNPs) in risk for D-TGA. METHODS AND RESULTS: We conducted a genome-wide association study in an international set of 1,237 patients with D-TGA and identified a genome-wide significant susceptibility locus on chromosome 3p14.3, which was subsequently replicated in an independent case-control set (rs56219800, meta-analysis P=8.6x10 CONCLUSIONS: This work provides support for a polygenic architecture in D-TGA and identifies a susceptibility locus on chromosome 3p14.3 nea

Prenatal Diagnosis of Transposition of the Great Arteries Reduces Postnatal Mortality: A Population-Based Study.

BACKGROUND: Transposition of the great arteries (TGA) may present as a life-threatening neonatal malformation. Although prenatal detection facilitates the perinatal management, the impact on outcome is controversial. METHODS: This study reviewed the differences in prenatal diagnosis of TGA from 2009 to 2014 among the 5 geographic areas in Ontario and compared the management, morbidity, and mortality among neonates with a prenatal (prenatal cohort; n = 70) vs a postnatal (postnatal cohort; n = 76) anomaly diagnosis. Cases were identified from prospective databases of the provincial cardiac tertiary centres and the coroner\u27s office. RESULTS: Prenatal TGA detection rates varied significantly among areas (median: 50%; range: 14% to 72%; P = 0.03). Compared with the postnatal cohort, time from birth to tertiary care admission (1.4 vs 10.4 hours, P \u3c 0.001), prostaglandin therapy (0.1 vs 5.3 hours; P \u3c 0.001), balloon atrial septostomy (5.3 vs 14.9 hours; P CONCLUSIONS: Prenatal diagnosis of TGA significantly shortened time intervals from birth to neonatal care and surgery and was associated with improved survival. The prenatal detection rate of TGA in Ontario was low (50% or less) outside of Metropolitan Toronto, suggesting the need for new strategies to further improve intraprovincial detection rates

Association between maternal marginalization and infants born with congenital heart disease in Ontario Canada

Abstract Background This study aims to evaluate the impact of socioeconomic status (SES) on the risk of congenital heart disease (CHD) since previous studies have yielded inconsistent results. Methods We conducted a population-based retrospective cohort study, including all singleton live and still births in Ontario hospitals from April 1, 2012, to March 31, 2018. We used linked records from the Better Outcomes Registry & Network Information System, the Canadian Institute for Health Information databases, and the Ontario Marginalization Index (ON_Marg). ON_Marg was estimated at a dissemination area level using Canadian Census 2016 data and categorized into quintiles. Multivariable logistic regression models were performed to examine the relationships between four ON_Marg indices (material deprivation, dependency, ethnic concentration, residential instability), as proxies for maternal SES and the risk of infant CHD. We adjusted for maternal age at birth, assisted reproductive technology, obesity, pre-existing health conditions, substance use during pregnancy, mental health conditions before and during pregnancy, rural residence, and infant’s sex in the analysis. Results Among the cohort of 776,799 singletons, 9,359 infants had a diagnosis of CHD. Of those, 3,069 were severe CHD and 493 cases were single ventricle CHD. The prevalence of all infant CHD types was higher for males relative to females. Compared to mothers living in neighbourhoods with the lowest material deprivation, mothers with highest material deprivation had a 27% (adjusted OR = 1.27; 95% CI: 1.18–1.37) higher odds of having an infant diagnosed with CHD. Mothers living in neighbourhoods with the highest minority ethnic and immigrant concentration tend to have infants with 11% lower odds of CHD (adjusted OR = 0.89; 95% CI: 0.82–0.97) as compared to those living in the least ethnically diverse communities. Maternal dependency and residential stability quintiles were not significantly associated with the risk of CHD. Conclusion Higher maternal material deprivation was associated with increasing odds of infant CHD, whereas neighbourhood minority ethnic concentration was inversely associated with the odds of infant CHD. Our study further confirms that poverty is associated with CHD development. Future investigations might focus on the causal pathways between social deprivation, immigrant status, ethnicity, and the risk of infant CHD

Impacting child health outcomes in congenital heart disease: Cluster randomized controlled trial protocol of in-clinic physical activity counselling.

BACKGROUND: Most (\u3e90%) children with congenital health defects are not active enough for optimal health. Proactively promoting physical activity during every clinic visit is recommended, but rarely implemented due to a lack of appropriate resources. METHODS: This cluster randomized controlled trial will implement an evidence-based, multi-faceted physical activity intervention. All eligible patients at small (London, ON), medium (Ottawa, ON) and large (Edmonton, AB) pediatric cardiac clinics will be approached, with randomization to intervention/control by clinic and week. Intervention patients will be counselled with 5 key physical activity messages, have questions about physical activity answered, and have access to a custom web site with personalized activity suggestions and support from a Registered Kinesiologist. The primary outcome is daily physical activity (number of steps, minutes of moderate-to-vigorous activity) assessed via pedometer one week per month for 6-months. Standardized questionnaires assess activity motivation and quality of life at baseline and end of study. Healthcare outcomes will be clinic visit time and contacts for physical activity concerns. Repeated measures ANCOVA will compare control/intervention pedometer outcomes, adjusting for covariates (alpha=0.05). CONCLUSIONS: This trial aims to determine whether providing resources and protocols enables clinicians to counsel about physical activity as part of every pediatric cardiology appointment. Evaluations of healthcare system impact and intervention delivery in small, medium and large clinics will assess applicability for implementation in all pediatric cardiac clinics. The impact on physical activity motivation and participation will evaluate the effectiveness of this standardized approach for increasing physical activity in children with congenital heart defects

Outcome of Antibody-Mediated Fetal Heart Disease With Standardized Anti-Inflammatory Transplacental Treatment.

Background Transplacental fetal treatment of immune-mediated fetal heart disease, including third-degree atrioventricular block (AVB III) and endocardial fibroelastosis, is controversial. Methods and Results To study the impact of routine transplacental fetal treatment, we reviewed 130 consecutive cases, including 108 with AVB III and 22 with other diagnoses (first-degree/second-degree atrioventricular block [n=10]; isolated endocardial fibroelastosis [n=9]; atrial bradycardia [n=3]). Dexamethasone was started at a median of 22.4 gestational weeks. Additional treatment for AVB III included the use of a β-agonist (n=47) and intravenous immune globulin (n=34). Fetal, neonatal, and 1-year survival rates with AVB III were 95%, 93%, and 89%, respectively. Variables present at diagnosis that were associated with perinatal death included an atrial rate &lt;90&nbsp;beats per minute (odds ratio [OR], 258.4; 95% CI, 11.5-5798.9; P&lt;0.001), endocardial fibroelastosis (OR, 28.9; 95% CI, 1.6-521.7; P&lt;0.001), fetal hydrops (OR, 25.5; 95% CI, 4.4-145.3; P&lt;0.001), ventricular dysfunction (OR, 7.6; 95% CI, 1.5-39.4; P=0.03), and a ventricular rate &lt;45&nbsp;beats per minute (OR, 12.9; 95% CI, 1.75-95.8; P=0.034). At a median follow-up of 5.9&nbsp;years, 85 of 100 neonatal survivors were paced, and 1 required a heart transplant for dilated cardiomyopathy. Cotreatment with intravenous immune globulin was used in 16 of 22 fetuses with diagnoses other than AVB III. Neonatal and 1-year survival rates of this cohort were 100% and 95%, respectively. At a median age of 3.1&nbsp;years, 5 of 21 children were paced, and all had normal ventricular function. Conclusions Our findings reveal a low risk of perinatal mortality and postnatal cardiomyopathy in fetuses that received transplacental dexamethasone±other treatment from the time of a new diagnosis of immune-mediated heart disease