Herschel C. Rosenberg

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.

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 = 4.8 × 10−11). 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 = 2.2 × 10−16). 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.

Preservation of the metabolic rate of oxygen in preterm infants during indomethacin therapy for closure of the ductus arteriosus

Background:The aim of this study was to assess and quantify the effects of indomethacin on cerebral blood flow (CBF), oxygen extraction fraction (OEF), and cerebral metabolic rate of oxygen (CMRO2) in preterm infants undergoing treatment for a patent ductus arteriosus (PDA).Methods:CBF and CMRO2 were measured before and after the first dose of a 3-d course of indomethacin to close hemodynamically significant PDA in preterm neonates. Indocyanine-green (ICG) concentration curves were acquired before and after indomethacin injection to quantify CBF and CMRO2.Results:Eight preterm neonates (gestational age, 27.6 ± 0.5 wk; birth weight, 992 ± 109 g; 6 males:2 females) were treated at a median age of 4.5 d (range, 4–21 d). Indomethacin resulted in an average CBF decrease of 18% (pre- and post-CBF = 12.9 ± 1.3 and 10.6 ± 0.8 ml/100 g/min, respectively) and an OEF increase of 11% (pre- and post-OEF = 0.38 ± 0.02 and 0.42 ± 0.02, respectively) but no significant change in CMRO2 (pre- and post-CMRO2 = 0.83 ± 0.07 and 0.76 ± 0.07 ml O2/100 g/min, respectively). Corresponding mean blood pressure (BP), arterial oxygen saturation (SaO2), heart rate, and end-tidal carbon dioxide tension levels remained unchanged.Conclusion:Indomethacin resulted in significant reduction in CBF but did not alter CMRO2 because of a compensatory increase in OEF.

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.

Increasing the Detection Rate of Congenital Heart Disease During Routine Obstetric Screening Using Cine Loop Sweeps

The purpose of this study was to demonstrate an increase in the detection rate of fetal cardiac defects using 2 cine loop sweeps.

Indomethacin Induced and Prostaglandin Relieved Coarctation of the Aorta in Right Aortic Arch With Left Arterial Duct: a Case Report

We describe the case of an infant with DiGeorge syndrome born with a right aortic arch and left arterial duct. Despite the remote location of the right aortic arch from the left arterial duct, he developed coarctation of the aorta during treatment with indomethacin. This was relieved by prostaglandin treatment. This case highlights the fact that, even in the absence of an arterial duct, ductal tissue can still be present in the aorta, and cause coarctation when exposed to indomethacin. We also demonstrate the utility of prostaglandin for relief of this type of obstruction.

Images in CardiologyShone's Complex and Levoatriocardinal Vein: A Rare Association

![Figure][1] [![Graphic][3] ][3][![Graphic][4] ][4][![Graphic][5] ][5] A 10-week-old male infant was referred for a systolic heart murmur, mild congestive heart failure with tachypnea, tachycardia, mildly enlarged liver, and a chest x-ray showing an enlarged cardiac

Shone's Complex and Levoatriocardinal Vein: A Rare Association

![Figure][1] [![Graphic][3] ][3][![Graphic][4] ][4][![Graphic][5] ][5] A 10-week-old male infant was referred for a systolic heart murmur, mild congestive heart failure with tachypnea, tachycardia, mildly enlarged liver, and a chest x-ray showing an enlarged cardiac

Comment on: Interest of b-blockers in patients with right ventricular systemic dysfunction.

Dear Sir, Bouallal et al have touched on an important therapeutic dilemma in patients with reduced right ventricular function supporting systemic circulation. As they have mentioned, there exist no randomised clinical trial showing the benefit of beta-blockade in this group of patients. Hence, the recommendation to treat these patients with betablockers remains without any evidence. We recently published the results of a prospective, randomised, double-blind, placebo-controlled trial of beta-blockade on patients with operated tetralogy of Fallot and could not demonstrate a significant positive effect on right or left ventricular size and function, cardiorespiratory exercise capacity, or quality of life. Despite there being fundamental differences in the pathophysiology of right ventricular volume overload – e.g. in post-operative patients with tetralogy of Fallot – and right ventricular pressure overload in patients with the morphologic right ventricle functioning as the systemic ventricle, obviously the effect of beta-blockade on the right ventricle seems to be different from the effect on the left ventricle. We would like to address several methodological concerns in the paper by Bouallal et al. There is no established gold standard for non-invasive assessment of the right ventricle. The most reliable method is cardiac magnetic resonance imaging. Radionuclide ventriculography is an alternative method for this purpose, but it is less reliable than cardiac magnetic resonance imaging, especially in patients with right ventricular overload after surgery for congenital cardiac disease. Nichols et al therefore recommend that cardiac magnetic resonance imaging should be the first choice for evaluating patients with congenital cardiac disease. In the paper published by Bouallal et al, the assessment of right ventricle (preand post-beta blocker therapy) was done based on cardiac magnetic resonance imaging (in 10 patients) and Radionuclide ventriculography (in eight patients). Despite cardiac magnetic resonance imaging showing no change in right ventricular ejection fraction, Radionuclide ventriculography showed an improvement in ejection fraction from 41% to 49% (p 5 0.031). Including two different methods for assessment of right ventricular function is per se problematic, but the question remains which method is more reliable and which results should be emphasised. The neurohumoral status of these patients remained unchanged, as reflected by the brain natriuretic peptide level, and hence it is difficult to attribute the improvement in ejection fraction as measured by Radionuclide ventriculography to remodelling of the right ventricular myocardium due to beta blockade. Despite the study showing some improvement in subjectively felt physical activity, based on the New York Heart Association classification and Ability index, objectively measured cardiopulmonary capacity remains unchanged. Owing to the nature of study (not placebo controlled), it is impossible to rule out a placebo effect. If there remains a positive clinical effect that is not explained by better myocardial function or exercise capacity, the question is what it is. In our opinion, these beneficial effects that we also observed in our placebo-controlled study may be caused by effects of beta-blocker therapy on the autonomic nervous system. Probably these effects could potentially be revealed by analysis of heart rate variability. Unfortunately, these data are not available in patients with congenital cardiac disease. Last but not least, although appropriate statistical methods were employed, the small number of Correspondence to: K. Norozi, MD, FRCPC, Division of Paediatric Cardiology, Department of Paediatrics, University of Western Ontario, 800 Commissioners Road East, PO Box 5010, London, Ontario, N6A 5W9, Canada. Tel: 11 519 685 8500 ext. 56062; Fax: 11 519 685 8156; E-mail: kambiz.norozi@ lhsc.on.ca