Aortic perfusion score for pulmonary atresia with intact ventricular septum: An antegrade coronary perfusion scoring system that is predictive of need for transplant and mortality.

BACKGROUND: Pulmonary atresia with intact ventricular septum is a unique congenital malformation of the heart in which patients may undergo single-, two- or 1½- ventricle repair. Size of the tricuspid valve annulus, morphology of the right ventricle and presence of ventriculocoronary connections can all impact the selection of appropriate palliative strategy. We developed the aortic perfusion score, a novel scoring system based on anterograde coronary perfusion with the aim of being able to identify patients at risk for death or transplant. METHODS: A retrospective study was conducted. Patients were included if an initial catheterization was done prior to any intervention. Each patient was assigned an aortic perfusion score based on the amount of antegrade perfusion to the four main coronary arteries. Various characteristics, including aortic perfusion score, were compared between those who required transplant or died during follow-up vs those who did not. Receiver operator curve analysis was done to determine a cutoff point predictive of a composite endpoint of death or transplant. RESULTS: A total of 64 patients were included in the analysis with 10 reaching the composite outcome. An aortic perfusion score of 227.5 predicted the endpoint with a sensitivity of 90% and a specificity of 83%. For each 1-point increase in the APS, the odds of death or transplant decreased by 1.7%. CONCLUSION: The aortic perfusion score can be used to predict a composite endpoint of death or transplant and may be helpful in selecting patients that should be listed for transplant.

Factors influencing bacteraemia in patients with isomerism and CHD: the effects of functional splenic status and antibiotic prophylaxis.

BACKGROUND: "Heterotaxy syndrome", best segregated as isomerism, is characterised by laterality defects of the thoraco-abdominal organs, causing functional impairment. In particular, the spleen is frequently affected, increasing susceptibility to bacteraemia. This study explored factors that may increase the risk of bacteraemia in patients with isomerism. METHODS: We identified patients with CHD and isomerism. Review of outpatient, inpatient, and surgical records was conducted to collect data and determine trends in the cohort. A Cox regression analysis was conducted to determine factors influencing freedom from bacteraemia (Fig 1). RESULTS: We identified 83 patients with CHD and isomerism - 17 (20%) who had documented episodes of bacteraemia with a total of 21 episodes. A majority (86%) were nosocomial. The median age at the time of bacteraemia was 4 months. Although splenic anatomy did appear to influence the risk of bacteraemia in univariate analysis, this significance was lost with multivariate analysis. None of the other factors was significantly associated in either univariate or multivariate analysis. CONCLUSION: Specific factors such as splenic anatomy, atrial appendage isomerism, and antibiotic prophylaxis status are not significantly associated with the risk of bacteraemia in patients with CHD and isomerism. Nosocomial infections represent a majority of bacteraemia in these patients.

Predicting the Need for Neoaortic Arch Intervention in Infants with Hypoplastic Left Heart Syndrome Through the Glenn Procedure.

Neoaortic recoarctation is present in up to over one-third of patients having undergone the Norwood procedure for hypoplastic left heart syndrome. Some of these patients will require reintervention by catheterization or surgery through the time of the Glenn procedure. Echocardiography and catheterization are often utilized in this period to assess hemodynamics although no specific criteria have been identified to predict whether and when neoaortic arch reintervention will be needed. We sought to identify predictors, including but not limited to echocardiographic and catheterization gradients, to predict such intervention. A retrospective analysis was conducted including patients with hypoplastic left heart syndrome. Patients with significantly comorbid lesions such as isomerism, anomalous pulmonary venous connections, and significant atrioventricular valve insufficiency were excluded as were patients without interstage echocardiographic and catheterization data. Receiver operator curve analysis was performed to establish peak-value gradients by echocardiography and catheterization that were predictive of neoaortic reintervention from the time of the Norwood through the time of the Glenn. These values were then entered into a multivariate regression with several other factors to determine what factors were predictive of need for such intervention. Bland-Altman analysis was conducted to compare echocardiographic and catheterization gradients. A peak echocardiographic gradient of 26 mmHg (100 % sensitivity, 85 % specificity) and a peak-to-peak catheterization gradient of 8.5 mm Hg (83 % sensitivity, 86 % specificity) were found to be predictive of need for neoaortic arch reintervention after multivariate analysis. Echocardiographic and catheterization gradients were found to have poor correlation with one another. A peak gradient of 26 mmHg or greater by echocardiography and a peak-to-peak gradient of 8.5 mmHg or greater by catheterization after the Norwood but prior to the Glenn are predictive of need for neoaortic reintervention through the time of the Glenn hospitalization.

Impact of MYH6 variants in hypoplastic left heart syndrome.

Hypoplastic left heart syndrome (HLHS) is a clinically and anatomically severe form of congenital heart disease (CHD). Although prior studies suggest that HLHS has a complex genetic inheritance, its etiology remains largely unknown. The goal of this study was to characterize a risk gene in HLHS and its effect on HLHS etiology and outcome. We performed next-generation sequencing on a multigenerational family with a high prevalence of CHD/HLHS, identifying a rare variant in the α-myosin heavy chain (MYH6) gene. A case-control study of 190 unrelated HLHS subjects was then performed and compared with the 1000 Genomes Project. Damaging MYH6 variants, including novel, missense, in-frame deletion, premature stop, de novo, and compound heterozygous variants, were significantly enriched in HLHS cases (P < 1 × 10-5). Clinical outcomes analysis showed reduced transplant-free survival in HLHS subjects with damaging MYH6 variants (P < 1 × 10-2). Transcriptome and protein expression analyses with cardiac tissue revealed differential expression of cardiac contractility genes, notably upregulation of the ß-myosin heavy chain (MYH7) gene in subjects with MYH6 variants (P < 1 × 10-3). We subsequently used patient-specific induced pluripotent stem cells (iPSCs) to model HLHS in vitro. Early stages of in vitro cardiomyogenesis in iPSCs derived from two unrelated HLHS families mimicked the increased expression of MYH7 observed in vivo (P < 1 × 10-2), while revealing defective cardiomyogenic differentiation. Rare, damaging variants in MYH6 are enriched in HLHS, affect molecular expression of contractility genes, and are predictive of poor outcome. These findings indicate that the etiology of MYH6-associated HLHS can be informed using iPSCs and suggest utility in future clinical applications.

Dual-Axis Rotational Angiography is Safe and Feasible to Detect Coronary Allograft Vasculopathy in Pediatric Heart Transplant Patients: A Single-Center Experience.

Coronary allograft vasculopathy (CAV) is the leading cause of graft failure in pediatric heart transplant recipients, also adding to mortality in this patient population. Coronary angiography is routinely performed to screen for CAV, with conventional single-plane or bi-plane angiography being utilized. Dual-axis rotational coronary angiography (RA) has been described, mostly in the adult population, and may offer reduction in radiation dose and contrast volume. Experience with this in the pediatric population is limited. This study describes a single-institution experience with RA for screening for CAV in pediatric patients. The catheterization database at our institution was used to identify pediatric heart transplant recipients having undergone RA to screen for CAV. Procedural data including radiation dose, fluoroscopy time, contrast volume, and procedure time were collected for each catheterization. The number of instances in which RA was not successful, ECG changes were present, and CAV was detected were also collected for each catheterization. A total of 97 patients underwent 345 catheterizations utilizing RA. Median radiation dose-area product per kilogram was found to be 341.7 (mGy cm(2)/kg), total air kerma was 126.8 (mGy), procedure time was 69 min, fluoroscopy time was 9.9 min, and contrast volume was 13 ml. A total of 17 (2 %) coronary artery injections out of 690 could not be successfully imaged using RA. A total of 14 patients had CAV noted at any point, 10 of whom had progressive CAV. Electrocardiographic changes were documented in a total of 10 (3 %) RA catheterizations. Procedural characteristics did not differ between serial catheterizations. RA is safe and feasible for CAV screening in pediatric heart transplant recipients while offering coronary imaging in multiple planes compared to conventional angiography.

Determining bronchial morphology for the purposes of segregating so-called heterotaxy.

UNLABELLED: Introduction Heterotaxy is a unique clinical entity in which lateralisation of the thoraco-abdominal organs is abnormal, typically with isomerism of the bronchial tree and atrial appendages. This study was carried out to determine whether routine clinical imaging such as chest radiographs, angiographic images, and CT/MRI can determine bronchial isomerism, and how sidedness of bronchial isomerism correlates with overall features anticipated in hearts with isomeric atrial appendages. Methods and results We identified 73 patients with heterotaxy, in whom imaging clearly demonstrated the bronchial tree, seen at our institution since 1998. We calculated bronchial angles and lengths using all the available imaging modalities to determine the presence and sidedness of bronchial isomerism. This was then compared with the anticipated presence of isomeric atrial appendages based on the overall clinical findings, as the appendages themselves had not specifically been imaged. The ratio of bronchial lengths revealed bronchial isomerism in all patients, with bronchial angles permitting distinction of right as opposed to left isomerism. We noted discordances between the identified bronchial isomerism and the presumed arrangement of the atrial appendages in nearly 20% of the patients in our cohort. CONCLUSION: Routine clinical imaging with chest radiographs, angiographic imaging, and CT/MRI can determine the presence of bronchial isomerism in patients with so-called heterotaxy. Right as opposed to left isomerism can be distinguished based on bronchial angles. The finding of bronchial isomerism correlates well, but not totally, with the presumed isomerism of the atrial appendages as predicted from the identified intra-cardiac morphology.

Is Aortic Valve Leaflet Morphology Predictive of Outcome in Pediatric Aortic Valve Stenosis?

BACKGROUND: Initial palliative treatment of congenital aortic valve stenosis consists of either surgical commissurotomy or transcatheter balloon valvuloplasty. The basis for selection of primary approach usually is ill defined. It was hypothesized that aortic valve characteristics may be helpful in directing choice of intervention. This study assesses the impact of valve morphology on time to reintervention after catheter- or surgical-based therapy. METHODS: A retrospective review of preprocedural echocardiographic aortic outflow characteristics was compared with outcomes of primary surgical or balloon valve interventions. Characteristics studied included (1) annular dimension; (2) leaflet number; (3) leaflet excursion; and (4) degree of leaflet coaptation. Patients included those <20 years with a primary diagnosis of aortic stenosis (AS) and no other hemodynamically significant lesions at our institutions from 2000 to 2011. A total of 102 patients were included, 31 classified as having critical and 71 as having noncritical aortic stenosis. Of the patients, 79 were male, and 50 underwent primary catheter intervention. Echo parameters were compared with procedural outcome as defined by death or need for reintervention. Receiver operator curves were utilized to determine the point within each morphologic feature where the greatest difference occurred. This was utilized as the distinguishing point within each the morphologic group. Analysis was conducted separately for critical and noncritical aortic stenosis. RESULTS: Kaplan-Meier analysis demonstrated no significant difference in time to reintervention or death whether initial palliation consisted of surgical commissurotomy or balloon valvuloplasty with respect to any of the morphologic characteristics studied. CONCLUSION: Patients with AS do equally well with surgical commissurotomy or balloon valvuloplasty as initial palliation. This holds true for those with either critical or noncritical aortic stenosis. Valve morphology did not help in selection of initial palliative strategy. Current technologies should enable an improved selection of initial palliative approach through thoughtful, randomized trials.

Addressing sexual health in congenital heart disease: when being the same isn't the same.

A larger number of individuals born with congenital heart disease is living into adolescence and young adulthood. With this comes the responsibility to counsel these patients regarding their sexual and reproductive health. This study utilizes representative data from the National Health and Nutrition Examination Survey to compare sexual measures including percentage of that sexually active, age of first sexual activity, number of sexual partners, condom use, and history of sexually transmitted diseases in those with and without congenital heart disease. A total of 1086 patients (1057 without congenital heart disease and 29 with congenital heart disease) were included in this study. Likelihood of being sexually active, age of first sexual intercourse, and condom use did not differ significantly between the two groups after multivariate analysis. Incidence of sexually transmitted disease did not differ between the two groups after multivariate analysis except for genital warts. There are no major differences in sexual measures between those with and without congenital heart disease. The absence of significant differences in sexual measures in those with congenital heart disease compared with the general population places this group of individuals at increased health risk known to occur with pregnancy.

Impact of pre-stage II hemodynamics and pulmonary artery anatomy on 12-month outcomes in the Pediatric Heart Network Single Ventricle Reconstruction trial.

OBJECTIVE: To compare the interstage cardiac catheterization hemodynamic and angiographic findings between shunt types for the Pediatric Heart Network Single Ventricle Reconstruction trial. The trial, which randomized subjects to a modified Blalock-Taussig shunt (MBTS) or right ventricle-to-pulmonary artery shunt (RVPAS) for the Norwood procedure, demonstrated the RVPAS was associated with a smaller pulmonary artery diameter but superior 12-month transplant-free survival. METHODS: We analyzed the pre-stage II catheterization data for the trial subjects. The hemodynamic variables and shunt and pulmonary angiographic data were compared between shunt types; their association with 12-month transplant-free survival was also evaluated. RESULTS: Of 549 randomized subjects, 389 underwent pre-stage II catheterization. A smaller size, lower aortic and superior vena cava saturation, and higher ventricular end-diastolic pressure were associated with worse 12-month transplant-free survival. The MBTS group had a lower coronary perfusion pressure (27 vs 32 mm Hg; P<.001) and greater pulmonary blood flow/systemic blood flow ratio (1.1 vs 1.0, P=.009). A greater pulmonary blood flow/systemic blood flow ratio increased the risk of death or transplantation only in the RVPAS group (P=.01). The MBTS group had fewer shunt (14% vs 28%, P=.004) and severe left pulmonary artery (0.7% vs 9.2%, P=.003) stenoses, larger mid-main branch pulmonary artery diameters, and greater Nakata indexes (164 vs 134, P<.001). CONCLUSIONS: Compared with the RVPAS subjects, the MBTS subjects had more hemodynamic abnormalities related to shunt physiology, and the RVPAS subjects had more shunt or pulmonary obstruction of a severe degree and inferior pulmonary artery growth at pre-stage II catheterization. A lower body surface area, greater ventricular end-diastolic pressure, and lower superior vena cava saturation were associated with worse 12-month transplant-free survival.

Stenting of the right ventricular outflow tract in the high-risk infant with cyanotic teratology of Fallot.

Neonatal tetralogy of Fallot (TOF) repair carries an increased risk of low birthweight or premature infants. Studies are investigating stents in the right ventricular outflow tract (RVOT) as an alternative to aortopulmonary shunts. The authors review their institutional experience with RVOT stenting in the high-risk infant with TOF. Data on sequential patients who received RVOT stents were reviewed, with collection of their surgical, echocardiographic, and catheterization data. Size-matched control subjects were identified and outcomes compared. Six infants went to the catheterization lab for RVOT stenting from 2008 to 2010. Five of these patients had placement of an RVOT stent after balloon dilation. The median saturations were 71% on 48% fraction of inspired oxygen (FiO2), with improvement to 94% (p < 0.001) on 39% FiO2 24 h after stent placement. As shown by echocardiography, the diameter of the median right pulmonary artery (RPA) was 2.6 mm (z-score, -3.3), and the diameter of the left pulmonary artery (LPA) was 2.0 mm (z-score, -4.5). Repeat echocardiography before surgery showed a statistically significant increase in RPA and LPA size as well as a modified McGoon ratio (p < 0.05). Four of the five patients subsequently underwent TOF repair. No stent fractures occurred. One patient had repair 10 days after stent placement secondary to stent malposition and tricuspid valve injury. The authors' experience with stents in the RVOT of TOF patients has yielded good results, with significant improvement in oxygen saturations. Patients had successful elective surgical repair and stent removal without longer cardiopulmonary bypass times or recognizable complications compared with shunted patients.

Intervention for recoarctation in the single ventricle reconstruction trial: incidence, risk, and outcomes.

BACKGROUND: Recoarctation after the Norwood procedure increases risk for mortality. The Single Ventricle Reconstruction (SVR) trial randomized subjects with a single right ventricle undergoing a Norwood procedure to a modified Blalock-Taussig shunt or a right ventricle-pulmonary artery shunt. We sought to determine the incidence of recoarctation, risk factors, and outcomes in the SVR trial. METHODS AND RESULTS: Recoarctation was defined by intervention, either catheter based or surgical. Univariate analysis and multivariable Cox proportional hazard models were performed with adjustment for center. Of the 549 SVR subjects, 97 (18%) underwent 131 interventions (92 balloon aortoplasty, 39 surgical) for recoarctation at a median age of 4.9 months (range, 1.1-10.5 months). Intervention typically occurred at pre-stage II catheterization (n=71, 54%) or at stage II surgery (n=38, 29%). In multivariable analysis, recoarctation was associated with the shunt type in place at the end of the Norwood procedure (hazard ratio, 2.0 for right ventricle-pulmonary artery shunt versus modified Blalock-Taussig shunt; P=0.02), and Norwood discharge peak echo-Doppler arch gradient (hazard ratio, 1.07 per 1 mm Hg; P<0.01). Subjects with recoarctation demonstrated comorbidities at pre-stage II evaluation, including higher pulmonary arterial pressures (15.4±3.0 versus 14.5±3.5 mm Hg; P=0.05), higher pulmonary vascular resistance (2.6±1.6 versus 2.0±1.0 Wood units·m(2); P=0.04), and increased echocardiographic volumes (end-diastolic volume, 126±39 versus 112±33 mL/BSA(1.3), where BSA is body surface area; P=0.02). There was no difference in 12-month postrandomization transplantation-free survival between those with and without recoarctation (P=0.14). CONCLUSIONS: Recoarctation is common after Norwood and contributes to pre-stage II comorbidities. Although with intervention there is no associated increase in 1-year transplantation/mortality, further evaluation is warranted to evaluate the effects of associated morbidities.

Dual-axis rotational coronary angiography: a new technique for detecting graft coronary vasculopathy in pediatric heart transplant recipients.

Annual surveillance coronary angiograpyhy to screen for graft coronary vasculopathy is routine practice after orthotopic heart transplantation. Traditionally, this is performed with direct coronary angiography using static single-plane or biplane angiography. Recently, technological advances have made it possible to perform dual-axis rotational coronary angiography (RA). This technique differs from standard static single-plane or biplane angiography in that a single detector is preprogrammed to swing through a complex 80° arc during a single injection. It has the advantage of providing a perspective of the vessels from a full arc of images rather than from one or two static images per contrast injection. The current study evaluated two coronary angiography techniques used consecutively at a single center to evaluate pediatric heart transplant recipients for graft coronary vasculopathy. A total of 23 patients underwent routine coronary angiography using both biplane static coronary angiography (BiP) and RA techniques at the Children's Hospital of Wisconsin from February 2009 to September 2010. Demographic and procedure data were collected from each procedure and analyzed for significance utilizing a Wilcoxon rank sum test. No significant demographic or procedural differences between the BiP and the RA procedures were noted. Specific measures of radiation dose including fluoroscopy time and dose area product were similar among the imaging techniques. The findings show that RA can be performed safely and reproducibly in pediatric heart transplant recipients. Compared with standard BiP, RA does not increase radiation exposure or contrast use and in our experience has provided superior angiographic imaging for the evaluation of graft coronary vasculopathy.

Including aortic valve morphology in computational fluid dynamics simulations: initial findings and application to aortic coarctation.

Computational fluid dynamics (CFD) simulations quantifying thoracic aortic flow patterns have not included disturbances from the aortic valve (AoV). 80% of patients with aortic coarctation (CoA) have a bicuspid aortic valve (BAV) which may cause adverse flow patterns contributing to morbidity. Our objectives were to develop a method to account for the AoV in CFD simulations, and quantify its impact on local hemodynamics. The method developed facilitates segmentation of the AoV, spatiotemporal interpolation of segments, and anatomic positioning of segments at the CFD model inlet. The AoV was included in CFD model examples of a normal (tricuspid AoV) and a post-surgical CoA patient (BAV). Velocity, turbulent kinetic energy (TKE), time-averaged wall shear stress (TAWSS), and oscillatory shear index (OSI) results were compared to equivalent simulations using a plug inlet profile. The plug inlet greatly underestimated TKE for both examples. TAWSS differences extended throughout the thoracic aorta for the CoA BAV, but were limited to the arch for the normal example. OSI differences existed mainly in the ascending aorta for both cases. The impact of AoV can now be included with CFD simulations to identify regions of deleterious hemodynamics thereby advancing simulations of the thoracic aorta one step closer to reality.

Leftward displacement of septum primum in hypoplastic left heart syndrome.

Embryologic development of atrial septum primum antedates formation of the atrioventricular and semilunar valves. Leftward displacement of the superior attachment of septum primum (LDSP) has only been described in hypoplastic left heart syndrome (HLHS). This study reports the frequency of LDSP in HLHS and correlates LDSP with other echocardiographic features of HLHS. Preoperative echocardiograms for 72 consecutive patients with classic HLHS from 1996 to 2002 at Children's Hospital of Wisconsin were reviewed. One patient was excluded for inadequate imaging. Data for the 71 patients included the following: size, location, and Doppler gradient across the atrial septal defect (ASD); location of attachment of septum primum; size and patency of the aortic valve (AoV) annulus; size and patency of the mitral valve (MV) annulus; ascending aorta diameter (AAD); and left-ventricular end diastolic dimension (LVEDD). Patients were categorized into three groups: aortic atresia/mitral atresia (AA/MA), aortic atresia/mitral stenosis (AA/MS), and aortic stenosis/mitral stenosis (AS/MS). LDSP was seen in 46 of 71 patients (64 %). By diagnostic group, 32 of 35 patients with AA/MA had LDSP (91 %) compared with 10 of 19 AA/MS patients (53 %) and 4 of 17 AS/MS patients (24 %), p < 0.05. AoV patency was seen in 4 of 46 (9 %) patients with LDSP compared with 13 of 25 (52 %) patients with normal atrial attachment, p < 0.005. Mean left heart dimensions in infants with LDSP compared with normal attachment were as follows: AoV annulus 2.24 versus 3.83 mm, AAD 2.34 versus 4.1 mm, MV annulus 3.21 versus 6.48 mm, and LVEDD 6.38 versus 13.83 mm. By two-way analysis of variance of diagnostic category versus atrial septal attachment with interaction, MV annulus and AAD were independently predicted smaller by LDSP versus normal atrial attachment, p < 0.05. Nonsignificant factors included AoV annulus, LVEDD, ASD size, and Doppler gradient. LDSP correlates with more severe maldevelopment of the left heart in patients with HLHS. Because formation of septum primum precedes development and growth of the intracardiac valves, we speculate that LDSP may be an initiating event in the development of HLHS. In addition, prenatal identification of LDSP may help direct planning of potential in utero therapies.

Timing and technique of pulmonary valve replacement in the patient with tetralogy of Fallot.

Residual right ventricular (RV) outflow tract pathology is universal among patients with repaired tetralogy of Fallot, and pulmonary regurgitation (PR) is also commonly present. Although tolerated in early life, by the second decade of life PR is associated with an increased risk of death because of ventricular arrhythmias. Pulmonary valve replacement (PVR) is a safe procedure that will eliminate PR, but timing and indications are evolving. Patients with arrhythmias or prolonged QRS duration are candidates for PVR. Patients with symptomatic exercise intolerance are likely to have improvement in symptoms and quality of life and should be offered PVR. Cardiac magnetic resonance has become an essential component of the management of the patient with tetralogy of Fallot with PR, and has identified the potential for and limitations of RV remodeling following PVR. Among patients with severe RV enlargement, particularly those with diminished RV or left ventricular function, there is an increased risk of adverse events and even asymptomatic patients with severe PR should be considered for PVR. Valve replacement is accomplished with homografts or heterografts, either stented bioprosthetic valves or valved conduits. In a retrospective analysis of the Children's Hospital of Wisconsin experience with PVR, there was no difference in survival or freedom from reintervention between heterografts and homografts.

Human gene copy number spectra analysis in congenital heart malformations.

The clinical significance of copy number variants (CNVs) in congenital heart disease (CHD) continues to be a challenge. Although CNVs including genes can confer disease risk, relationships between gene dosage and phenotype are still being defined. Our goal was to perform a quantitative analysis of CNVs involving 100 well-defined CHD risk genes identified through previously published human association studies in subjects with anatomically defined cardiac malformations. A novel analytical approach permitting CNV gene frequency "spectra" to be computed over prespecified regions to determine phenotype-gene dosage relationships was employed. CNVs in subjects with CHD (n = 945), subphenotyped into 40 groups and verified in accordance with the European Paediatric Cardiac Code, were compared with two control groups, a disease-free cohort (n = 2,026) and a population with coronary artery disease (n = 880). Gains (≥200 kb) and losses (≥100 kb) were determined over 100 CHD risk genes and compared using a Barnard exact test. Six subphenotypes showed significant enrichment (P ≤ 0.05), including aortic stenosis (valvar), atrioventricular canal (partial), atrioventricular septal defect with tetralogy of Fallot, subaortic stenosis, tetralogy of Fallot, and truncus arteriosus. Furthermore, CNV gene frequency spectra were enriched (P ≤ 0.05) for losses at: FKBP6, ELN, GTF2IRD1, GATA4, CRKL, TBX1, ATRX, GPC3, BCOR, ZIC3, FLNA and MID1; and gains at: PRKAB2, FMO5, CHD1L, BCL9, ACP6, GJA5, HRAS, GATA6 and RUNX1. Of CHD subjects, 14% had causal chromosomal abnormalities, and 4.3% had likely causal (significantly enriched), large, rare CNVs. CNV frequency spectra combined with precision phenotyping may lead to increased molecular understanding of etiologic pathways.

Exploring the environmental and genetic etiologies of congenital heart defects: the Wisconsin Pediatric Cardiac Registry.

INTRODUCTION: The Wisconsin Pediatric Cardiac Registry (WPCR) collects information on infants born in the state of Wisconsin with structural congenital heart disease (CHD). METHODS: The WPCR actively ascertains CHD cases in the state of Wisconsin. Cases must be conceived and born in Wisconsin after January 1, 2000. Once ascertained, subjects are approached to participate in genetic sampling and completion of a questionnaire that assesses family history of CHD, maternal health, and environmental exposures before pregnancy and during the first trimester. In 2009, the WPCR underwent a transition to a new database and from a paper questionnaire to a Web-based questionnaire. RESULTS: The WPCR has screened over 5,100 children and has ascertained 4,919 cases of CHD in the state of Wisconsin during the years 2000 to 2009. During this interval, 1,982 completed questionnaires and 1,062 DNA samples have been obtained from consented subjects. Another 1,774 DNA samples have been obtained from blood relatives of CHD subjects. DISCUSSION: The WPCR operates as a specialized resource of genetic and environmental information on children with CHD for researchers focusing on the multifactorial causes of CHD.

Aortic exclusion: a method of handling aortic insufficiency in the pediatric population needing mechanical circulatory support.

Aortic insufficiency (AI) is generally regarded as a contraindication for mechanical circulatory support in children. In the current Berlin EXCOR trial, moderate to severe AI is an exclusion criterion. There are reports in the literature of successful mechanical circulatory support (MCS) in adult patients with significant AI via "aortic exclusion" or bioprosthetic aortic valve replacement. We report the first case of aortic exclusion in an infant with moderate to severe aortic insufficiency in need of MCS.

Modeling geographic risk of complex congenital heart defects in Eastern Wisconsin.

BACKGROUND: Geographic variation may be an indicator of risk factors for birth defects. This study models the geographic distribution of three complex congenital heart defects (CHDs) in eastern Wisconsin, and evaluates effects of demographic census variables linked to geographic location. METHODS: Cases of Hypoplastic Left Heart Syndrome (HLHS), Tetralogy of Fallot (TOF) and d-Transposition of the Great Arteries (d-TGAs) born between1995 and 2004 were identified from three medical centers serving eastern Wisconsin. Case diagnoses were assigned by a pediatric cardiologist using echocardiographic records. Births by ZIP code were obtained from the State of Wisconsin. ZIP Code demographic variables were derived from 2000 census data. Numbers of cardiac defects by ZIP code were modeled using cluster analysis and Poisson generalized additive models (GAMs) for spatial coordinates including all and white only cases (excluding trisomies). GAM analyses were repeated adjusting for census variables. RESULTS: Four hundred forty-eight cases were ascertained. A significant south-to-north spatial gradient for HLHS, TOF, and combined CHDs, but not d-TGAs was identified. This gradient remained significant when census variables were included in the model for the full sample. In the analysis excluding non-white cases, findings were the same for TOF, combined CHDs, and d-TGAs. However, the geographic gradient for HLHS was not significant in the adjusted model. CONCLUSIONS: A south-to-north gradient was apparent for two of three complex CHDs in eastern Wisconsin. For white cases, demographic variation seems to explain some of this spatial gradient in HLHS. Further studies are needed to confirm demographic and other risk factors underlying this geographic gradient.