Jane Lougheed

Acquired right ventricular outflow tract obstruction in the recipient twin in twin-twin transfusion syndrome

OBJECTIVESnThe goal of this study was to determine the prevalence and evolution of acquired right ventricular outflow tract obstruction (RVOTO) in the recipient twin in twin-twin transfusion syndrome (TTTS).nnnBACKGROUNDnTwin-twin transfusion syndrome complicates 4% to 26% of diamniotic monochorionic twin gestations and is associated with high fetal morbidity and mortality. Cardiac dysfunction and biventricular hypertrophy may develop in the recipient twin with the potential for RVOTO.nnnMETHODSnThis was a retrospective review of a two-center experience of TTTS to describe the prevalence and evolution of acquired RVOTO in the recipient twin. Right ventricular outflow tract obstruction was diagnosed or excluded by fetal or postnatal echocardiography or clinical assessment.nnnRESULTSnOf 73 twin pregnancies with TTTS identified between 1994 to 1998, a total of seven (9.6%) were complicated by RVOTO in the recipient twin: two subvalvar/muscular, four valvar and one combined. Of 44 pregnancies with fetal echo, six had in utero RVOTO with antegrade flow diagnosed at gestational ages ranging from 19 to 27 weeks. In utero progression occurred in four cases over a period of four to eight weeks, with the development of RVOT atresia by delivery. Postnatal progression of RVOTO occurred in two cases, one of which required pulmonary balloon valvuloplasty at age two years. Postnatal regression of subvalvar RVOTO occurred in two cases in early infancy. Death related directly or indirectly to the RVOTO occurred in all four patients who developed complete RVOT obliteration.nnnCONCLUSIONSnRight ventricular outflow tract obstruction may occur in the recipient twin of at least 9% of pregnancies complicated by TTTS. Right ventricular outflow tract obstruction progression is common in utero and may worsen neonatal outcome.

Presentation, Diagnosis, and Medical Management of Heart Failure in Children: Canadian Cardiovascular Society Guidelines

Pediatric heart failure (HF) is an important cause of morbidity and mortality in childhood. This article presents guidelines for the recognition, diagnosis, and early medical management of HF in infancy, childhood, and adolescence. The guidelines are intended to assist practitioners in office-based or emergency room practice, who encounter children with undiagnosed heart disease and symptoms of possible HF, rather than those who have already received surgical palliation. The guidelines have been developed using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) methodology, and are accompanied by practical Recommendations for their application in the clinical setting, supplemented by online material. This work does not include Recommendations for advanced management involving ventricular assist devices, or other device therapies.

Impact of prenatal risk factors on congenital heart disease in the current era.

Background The healthcare burden related to congenital heart disease (CHD) is increasing with improving survival. We assessed changing trends in prenatal risk factors for CHD in the current era in a Canadian cohort. Methods and Results CHD patients <18 years old (n=2339) and controls without structural heart disease (n=199) were prospectively enrolled in an Ontario province‐wide biobank registry from 2008–2011. Family history, frequency of extra‐cardiac anomalies (ECAs), and antenatal risk factors were assessed. Temporal trends were analyzed and associations with CHD were measured using linear and logistic regression. Family history of CHD and frequency of major ECAs was higher in cases versus controls (P<0.001). Despite an increase in genetic testing in the recent era, only 9.5% of cases with CHD had a confirmed genetic diagnosis. Yield of genetic testing (ie, frequency of abnormal results) was higher in familial and syndromic cases. There was an increase in parental age at conception, maternal prepregnancy body mass index, maternal urinary tract infections, type 1 diabetes, and exposure to nonfertility medications during pregnancy from 1990–2011. Later year of birth, family history of CHD, presence of major ECAs, maternal smoking during pregnancy, and maternal medication exposure were associated with increased odds of CHD (P<0.05 for all). Advanced parental age was associated with increased odds of CHD caused by genetic abnormalities. Conclusions The increase in prenatal risk factors for CHD highlights the need for more rigorous ascertainment of genetic and environmental factors including gene‐environment interactions that contribute to CHD.

Genetic determinants of right-ventricular remodeling after tetralogy of Fallot repair.

Background:Hypoxia-inducible factor (HIF1A) regulates the myocardial response to hypoxia and hemodynamic load. We investigated the association of HIF1A variants with right-ventricular (RV) remodeling after tetralogy of Fallot (TOF) repair.Methods:Children with TOF were genotyped for three single-nucleotide polymorphisms in HIF1A. Genotypes were analyzed for association with RV myocardial protein expression and fibrosis at complete repair (n = 42) and RV dilation, fractional area change, and freedom from pulmonary valve/conduit replacement on follow-up.Results:In 180 TOF patients, mean age at repair was 1.0 ± 0.8 y with follow-up at 9.0 ± 3.5 y; 82% had moderate to severe pulmonary insufficiency. Freedom from RV reinterventions at 5, 10, and 15 y was 92, 84, and 67%, respectively. Patients with more functioning HIF1A alleles had higher transforming growth factor β1 expression and more fibrosis at initial repair as compared with controls (P < 0.05). During follow-up, patients with more functioning HIF1A alleles showed less RV dilation, better preservation of RV function, and greater freedom from RV reinterventions (P < 0.05). This was confirmed in a replication cohort of 69 patients.Conclusion:In children who have had TOF repair, a lower number of functioning HIF1A alleles was associated with RV dilation and dysfunction, suggesting that hypoxia adaptation in unrepaired TOF may influence RV phenotype after repair.

The Prevention of Congenital Anomalies with Periconceptional Folic Acid Supplementation

Large randomized trials have demonstrated the critical role of folic acid supplementation in the prevention of neural tube defects. Since 1992, a number of national and international professional societies have released guidelines recommending folic acid supplementation of at least 0.4 mg/day for all women of childbearing age or women planning pregnancies, and 4 mg/day for women with a previous infant with a neural tube defect. Furthermore, a reduction in the incidence of congenital cardiac and urologic anomalies has been demonstrated in some studies following periconceptional folic acid supplementation. There is growing evidence of a possible role of folic acid supplementation in the prevention of other congenital anomalies, including cardiac defects. Since 1998, mandatory fortification of certain foods with folate has been associated with at least a 54% reduction in the incidence of open neural tube defects, yet rates of periconceptional folic acid use remain suboptimal, especially in minority women. Innovative strategies in educating women, health-care providers, and pharmacists on the benefits of folic acid supplementation need to be explored. Mandatory folate fortification of foods needs to be defined and monitored.

Cardiac risk assessment before the use of stimulant medications in children and youth: A joint position statement by the Canadian Paediatric Society, the Canadian Cardiovascular Society, and the Canadian Academy of Child and Adolescent Psychiatry

Regulatory decisions and scientific statements regarding the management of attention-deficit hyperactivity disorder (ADHD) raise questions about the safety of medications and the appropriate pretreatment evaluation to determine suitability for treatment with medication. This is particularly true in the setting of known structural or functional heart disease. The present paper reviews the available data, including peer-reviewed literature, data from the United States Food and Drug Administration Web site on reported adverse reactions in children using stimulant medication, and Health Canada data on the same problem. A consensus-based guideline on appropriate assessment is provided, based on input from members of the Canadian Paediatric Society, the Canadian Cardiovascular Society and the Canadian Academy of Child and Adolescent Psychiatry, with specific expertise and knowledge in the areas of both ADHD and pediatric cardiology. The present statement advocates a thorough history and physical examination before starting stimulant medications, with an emphasis on the identification of risk factors for sudden death, but does not routinely recommend electrocardiographic screening or cardiac subspecialist consultation unless indicated by history or physical examination findings. A checklist for identifying children who are potentially at risk of sudden death (independent of ADHD or medications used to treat it) is provided. Although recommendations are based on the best evidence currently available, the committee further agrees that more research on this subject is necessary to optimize the approach to this common clinical scenario.

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 nonsyndromic 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 (OR): 1.52; 95% confidence interval (CI): 1.35–1.71; P = 4.8u2009×u200910−11). The enrichment was specific to AVSD probands, compared with a cohort without AVSD with tetralogy of Fallot (OR: 2.25; 95% CI: 1.84–2.76; P = 2.2u2009×u200910−16). Six genes (NIPBL, CHD7, CEP152, BMPR1a, ZFPM2, and MDM4) were enriched for rare variants in AVSD compared with controls, including three syndrome-associated genes (NIPBL, CHD7, and 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.Genet Med 18 2, 189–198.

The measurement of the QT and QTc on the neonatal and infant electrocardiogram: a comprehensive reliability assessment.

Background: An electrocardiogram has been proposed to screen for prolonged QT interval that may predispose infants to sudden death in the first year of life. Understanding the reliability of QT interval measurement will inform the design of a screening program.

Factors Influencing Participation in a Population- based Biorepository for Childhood Heart Disease

BACKGROUND: Consenting minors for genetics research and biobanking involves ethical and social challenges. We examined factors influencing participation rates in a population-based biorepository for childhood heart disease. METHODS: Individuals were prospectively enrolled across 7 centers in Ontario by using a standardized consent form. Individuals were approached for consent for the donation of blood/saliva (DNA), tissue, and skin from the affected individual for future genomics and stem cell research. Consent rates were compared between pediatric and adult patients and factors affecting consent were analyzed by using multiple logistic regression analysis. RESULTS: From 2008 to 2011, 3637 patients were approached. A total of 2717 pediatric patients consented (90% consent rate); mean age was 8.5 ± 5.8 years (57% male; 76% white). A total of 561 adult patients consented (92% consent rate, P = .071 versus pediatric). Factors associated with lower pediatric consent rates included younger age, race, absence of complex defects, and location of consent; these were not associated with adult consent rates. Leading causes for refusal of consent were lack of interest in research (43%), overwhelmed clinically (14%), and discomfort with genetics (11%). Concerns related to privacy, insurability, indefinite storage, and ongoing access to medical records were not the leading causes for refusal. CONCLUSIONS: The high pediatric consent rate (90%) was comparable with that of adults. Ethical, social, or legal issues were not the leading reasons for refusal of consent.

Update in Pediatric Cardiology

The field of pediatric cardiology has changed significantly over the past decade. The epidemiology of congenital heart disease (CHD) is shifting, with increased prenatal diagnosis, improved survival, and improved imaging and intervention techniques. Long term issues including neurodevelopmental outcome, exercise capacity, quality of life and reproduction have become more important as children survive their heart disease into adulthood. Neonatal oximetry screening is becoming routine practice to ensure that the majority of critical CHD is diagnosed as early as possible, as this has a positive impact on outcome. Imaging techniques in pediatric cardiology are evolving rapidly. Echocardiography remains the mainstay of imaging, with new techniques of 3D imaging and advanced function assessment adding to its utility. Cardiac MRI and CT are becoming important adjunct imaging techniques, particularly due the 3D and spatial information obtained. Cardiac catheterization with angiography is utilized less as a solely diagnostic technique, but has a substantial and increasing role in non-surgical intervention for CHD. Genetic testing in pediatric cardiology is adding yet further information regarding diagnosis, treatment options and prognosis in CHD, cardiomyopathies and cardiac channelopathies.