Home-Based Resistance Training Programme in Fontan Patients: It Is Feasible, Safe, and Efficient.

Background: Fontan physiology is characterized by a single functional systemic ventricle that reduces cardiac output adaptation and exercise capacity. Peripheral muscle pump is crucial for venous return, and resistance training of the peripheral muscles may be particularly beneficial for cardiac function in these patients. This study explores the feasibility of a training programme including safety and effectiveness, maximal exercise capacity, cardiorespiratory endurance, and quality of life in a Fontan population. Methods: Twelve Fontan patients (18-32 years old) with New York Heart Association functional classes I and II were recruited. The intervention was 12 weeks of home-based exercise programme of 3 sessions per week supervised online by a physiotherapist. Pre- and postintervention evaluations assessed lean body mass, segmental forces with a hand-held dynamometer, maximal oxygen consumption (VO2max), cardiovascular endurance, leg endurance with a 1-minute-sit-to-stand test, and quality of life with a 36-item Short-Form Survey. Results: A total of 11 of 12 participants completed 35 of 36 workouts, exceeding our 80% threshold for completion. No adverse events were reported. Leg muscle strength increased significantly (knee extensors improved by 22.8 ± 22.8 N m [17.7%], P = 0.019). Despite no change in VO2max, endurance time showed a significant improvement of 5.3 minutes (72%). Perceived physical condition evaluated with a self-perception scale improved significantly. There was no significant difference in the lean body mass and in quality of life. Conclusion: In this small group of post-Fontan patients with mild functional impairments, we describe a structured, accessible, and feasible home-based resistance training programme that seems safe and show improvements in strength and perceived physical condition.

Contexte: La physiologie qui découle de l'intervention de Fontan se caractérise par un cœur univentriculaire fonctionnel pour la circulation générale, ce qui réduit l'adaptation du débit cardiaque et la tolérance à l'effort. Le pompage par les muscles périphériques est essentiel au retour veineux, et un entraînement musculaire pourrait donc être bénéfique pour la fonction cardiaque des patients qui ont subi cette intervention. Dans notre étude, nous évaluons la possibilité de mettre en place un programme d'entraînement et examinons l'innocuité et l'efficacité d'un tel programme, la tolérance à l'effort maximal, l'endurance cardiorespiratoire et la qualité de vie chez des patients présentant une circulation de Fontan. Méthodologie: Nous avons recruté 12 patients (âgés de 18 à 32 ans) présentant une circulation de Fontan avec les classes fonctionnelles I et II selon la New York Heart Association. L'intervention prenait la forme d'un programme d'exercice à domicile de trois séances par semaine pendant douze semaines, sous la supervision en ligne d'un physiothérapeute. Les évaluations réalisées avant et après l'intervention incluaient la masse maigre, la force de différents segments corporels évaluée par un dynamomètre portatif, la consommation maximale d'oxygène (VO2max), l'endurance cardiovasculaire, l'endurance des jambes évaluées par un test du lever de la chaise d'une minute et un court questionnaire de 36 questions sur la qualité de vie. Résultats: Au total, 11 des 12 participants ont réalisé 35 entraînements sur 36, ce qui dépassait le seuil de réussite du programme établi à 80 %. Aucun effet indésirable n'a été signalé. La force des muscles des jambes a significativement augmenté (l'amélioration de la force des extenseurs des genoux s'élevait à 22,8 ± 22,8 N m [17,7 %] [p = 0,019]). Malgré une valeur de VO2max restée stable, le temps d'endurance s'est amélioré significativement, soit de 5,3 minutes (72 %). La perception de la condition physique, mesurée sur une échelle d'autoévaluation par les patients, s'est améliorée significativement. Aucune différence significative n'a été relevée dans la masse maigre et la qualité de vie des patients. Conclusion: Dans un petit groupe de patients ayant subi une intervention de Fontan et présentant une atteinte fonctionnelle légère, nous décrivons un programme structuré de musculation à domicile accessible et réalisable qui semble sécuritaire et qui a amélioré la force et de la perception de la condition physique des patients.

Diagnostic Efficacy of a Single-Lead Ambulatory 14-Day ECG Monitor in Symptomatic Children.

BACKGROUND: The CardioSTAT is a single-lead ambulatory electrocardiography monitor that has been validated for use in adult patients. Recording is made through 2 electrodes positioned in a lead-I configuration, and the device allows monitoring for 2, 7, or 14 days. We sought to investigate the efficacy of this device in children with paroxysmal palpitations. METHODS: In phase I, the quality of tracings from simultaneous CardioSTAT recordings and D1-lead recordings of a standard 12-lead electrocardiography machine in 23 children were compared. Phase II was a prospective observational cohort study comparing arrhythmia detection using the CardioSTAT vs currently used devices (24-hour Holter monitor and the Cardiomemo loop recorder) in 52 children complaining of palpitations. RESULTS: In Phase I, all but 3 rhythm strips were correctly identified. The pacing spikes on 3 strips were not adequately identified by the observers for the CardioSTAT recording. In Phase II, symptomatic episodes were reported in 42%, 73%, and 100% of subjects during monitoring with the Holter, Cardiomemo, and CardioSTATdevices, respectively. An abnormal rhythm was detected in 13%, 23%, and 35% of subjects by the Holter, Cardiomemo, and CardioSTAT monitors, respectively. The underlying rhythm during symptomatic events was determined in 90% of cases with the CardioSTAT monitor, whereas it was determined in only 19% and 29% of cases using the Holter and Cardiomemo monitors, respectively. CONCLUSIONS: The CardioSTAT monitor provided good-quality tracings and was superior to the 24-hour Holter monitor and the Cardiomemo loop recorder in determining the presence or absence of pathologic arrhythmia in the study cohort.

CONTEXTE: Le CardioSTAT est un moniteur d'électrocardiographie ambulatoire à dérivation unique dont l'utilisation a été validée chez les patients adultes. L'enregistrement se fait au moyen de 2 électrodes positionnées dans une configuration de type « dérivation I ¼, et l'appareil permet un suivi pendant 2, 7 ou 14 jours. Nous avons cherché à étudier l'efficacité de cet appareil chez les enfants atteints de palpitations paroxystiques. MÉTHODOLOGIE: Dans la phase I, la qualité des tracés provenant d'enregistrements simultanés de CardioSTAT et d'enregistrements de la dérivation I d'un appareil d'électrocardiographie standard à 12 dérivations a été comparée chez 23 enfants. La phase II était une étude de cohorte observationnelle prospective comparant la détection de l'arythmie à l'aide du moniteur CardioSTAT par rapport aux appareils utilisés actuellement (moniteur Holter à surveillance sur 24 heures et enregistreur d'événements portatif Cardiomémo) chez 52 enfants se plaignant de palpitations. RÉSULTATS: Dans la phase I, toutes les bandes d'enregistrement sauf trois ont été correctement identifiées. Les spicules de stimulation n'ont pas été correctement détectés par les observateurs sur trois bandes d'enregistrement du moniteur CardioSTAT. Dans la phase II, des épisodes symptomatiques ont été signalés chez 42 %, 73 % et 100 % des sujets pendant la surveillance avec les appareils Holter, Cardiomémo et CardioSTAT, respectivement. Un rythme anormal a été détecté chez 13 %, 23 % et 35 % des sujets par les moniteurs Holter, Cardiomémo et CardioSTAT, respectivement. Le rythme sous-jacent pendant les événements symptomatiques a été déterminé dans 90 % des cas avec le moniteur CardioSTAT, alors qu'il n'a été déterminé que dans 19 % et 29 % des cas, respectivement, avec les moniteurs Holter et Cardiomémo. CONCLUSIONS: Le moniteur CardioSTAT a fourni des tracés de bonne qualité et s'est révélé supérieur à l'appareil Holter à surveillance sur 24 heures et à l'enregistreur d'événements portatif Cardiomémo pour déterminer la présence ou l'absence d'arythmie pathologique dans la cohorte étudiée.

First-Degree Relatives Screening of Patients with Bicuspid Aortic Valve: Effectiveness and Feasibility in Pediatric Cardiology Daily Practice.

Bicuspid aortic valve (BAV) is the most common congenital heart disease. Since heritability is suspected, actual guidelines recommend to perform an echocardiographic assessment for first-degree relatives (FDR) of patient with BAV. This study aimed to assess the effectiveness and the feasibility of the current guidelines for the screening of FDR of patient with BAV in a pediatric cardiology daily practice. Consecutive patients with BAV and their FDR were prospectively included from January 2015 to March 2018 at Centre Hospitalier Universitaire de Laval, Quebec City (Canada). Data were retrospectively collected and analyzed. A total of 713 FDR of 213 consecutives index cases [median age: 11 (6-20) years] were studied. Up to 32 (6.6%) FDR had a BAV and 26 (5.4%) had an aortic valve dysfunction. A total of 14 (2.9%) FDR had an ascending aorta dilatation according to Z-score including 6 (1.2%) patients with an ascending aorta ≥ 45 mm. No statistically significant differences regarding BAV, aortic valve dysfunction and ascending aorta dilatation prevalence were identified between generations. Screening was done in 482 (67.6%), prescribed but not done in 134 (19%), not prescribed in 92 (13%) and declined in 5 (1%) FDR. The prevalence of BAV in FDR was similar to prospective adult studies and supports actual guidelines in pediatric cardiology practice. Ascending aorta dilatation was rare in our young population. Exhaustiveness and additional burden to implement current guidelines remain a challenge in daily practice.

Right atrial catheter "ghost" removal by cardiac surgery: A pediatric case series report.

Fibrin sheath formation around long-term indwelling central venous catheters is common and usually benign. Fibrin sheath can persist after catheter removal and rarely leads to complications. This is a report of three pediatric oncology patients that required cardiac surgery for cardiac embolization of a "ghost" catheter several years after catheter removal. One case required tricuspid valve replacement for complete tricuspid valve destruction and two had erosion through the atrial wall. The severity of these rare complications mandates follow-up of "ghost" catheters in pediatric oncology patients.

More Than 25 Years of Experience With the Ross Procedure in Children: A Single-Center Experience.

BACKGROUND: Aortic valve replacement in children represents an important challenge. Concerns regarding pulmonary autograft and homograft longevity requiring reoperations are well recognized. Very long-term outcomes after the Ross procedure are still unknown. We reviewed our experience with the Ross procedure, aiming to define very long-term survival rate and freedom from reintervention. METHODS: This was a single-center retrospective cohort including 63 consecutive children who underwent the Ross procedure. Median follow-up duration was 20.5 years. Time-related events were assessed using Kaplan-Meier estimator. RESULTS: There were 51 (81%) boys, mean age 10.1 ± 5.8 years. Isolated aortic stenosis was the most common diagnosis (n = 29, 46%) and 34 (54%) patients previously underwent cardiac surgery. There was 1 (1.6%) in-hospital death. Overall survival at 5, 15, and 25 years was 96.7%, 94.4%, and 94.4%, respectively. Freedom from any autograft-related reintervention was 98.1%, 86.4%, and 61.2% at 5, 15, and 25 years, respectively. Fifteen (24%) patients underwent autograft reoperations. Among them, 10 (67%) patients underwent valve-sparing autograft reoperation. Freedom from any pulmonary conduit reintervention was 93.2%, 58.2%, and 28.3% at 5, 15, and 25 years, respectively. Thirty (46.6%) patients underwent conduit reintervention (8 percutaneous, 22 surgical replacements). CONCLUSIONS: The pediatric Ross procedure is associated with excellent long-term survival. Ross-related reinterventions are more than twice as common on the pulmonary homograft than on the autograft.

Molecular Signature of CAID Syndrome: Noncanonical Roles of SGO1 in Regulation of TGF-ß Signaling and Epigenomics.

BACKGROUND & AIMS: A generalized human pacemaking syndrome, chronic atrial and intestinal dysrhythmia (CAID) (OMIM 616201), is caused by a homozygous SGO1 mutation (K23E), leading to chronic intestinal pseudo-obstruction and arrhythmias. Because CAID patients do not show phenotypes consistent with perturbation of known roles of SGO1, we hypothesized that noncanonical roles of SGO1 drive the clinical manifestations observed. METHODS: To identify a molecular signature for CAID syndrome, we achieved unbiased screens in cell lines and gut tissues from CAID patients vs wild-type controls. We performed RNA sequencing along with stable isotope labeling with amino acids in cell culture. In addition, we determined the genome-wide DNA methylation and chromatin accessibility signatures using reduced representative bisulfite sequencing and assay for transposase-accessible chromatin with high-throughput sequencing. Functional studies included patch-clamp, quantitation of transforming growth factor-ß (TGF-ß) signaling, and immunohistochemistry in CAID patient gut biopsy specimens. RESULTS: Proteome and transcriptome studies converge on cell-cycle regulation, cardiac conduction, and smooth muscle regulation as drivers of CAID syndrome. Specifically, the inward rectifier current, an important regulator of cellular function, was disrupted. Immunohistochemistry confirmed overexpression of Budding Uninhibited By Benzimidazoles 1 (BUB1) in patients, implicating the TGF-ß pathway in CAID pathogenesis. Canonical TGF-ß signaling was up-regulated and uncoupled from noncanonical signaling in CAID patients. Reduced representative bisulfite sequencing and assay for transposase-accessible chromatin with high-throughput sequencing experiments showed significant changes of chromatin states in CAID, pointing to epigenetic regulation as a possible pathologic mechanism. CONCLUSIONS: Our findings point to impaired inward rectifier potassium current, dysregulation of canonical TGF-ß signaling, and epigenetic regulation as potential drivers of intestinal and cardiac manifestations of CAID syndrome. Transcript profiling and genomics data are as follows: repository URL: https://www.ncbi.nlm.nih.gov/geo; SuperSeries GSE110612 was composed of the following subseries: GSE110309, GSE110576, and GSE110601.

Determination of peak cardiorespiratory fitness parameters in children: which averaging method should we use?

The purpose of this study was to identify which averaging methods most accurately measures peak cardiorespiratory fitness (CRF) parameters [peak O2 uptake (VO2), peak O2pulse and peak respiratory exchange ratio (RER)] in a sample of healthy children and adolescents. In this cross-sectional multicenter study, we recruited 278 healthy children aged 12-17 years. We compared the mean peak value of three CRF parameters using the recommended averaging methods (30-second block average) with alternative averaging methods such as moving averages or shorter smoothing periods. We also assessed averaging methods for accuracy by individually reviewing breath-by-breath scatter plots. The 30-second block average method resulted in a lower mean peak VO2 and in an increased proportion of underestimated peak values. Using a 30-second moving average significantly increased mean peak values which increased accuracy. Similar results were found for peak RER and peak O2pulse. In conclusion, the currently recommended averaging method (30-second block average) increased the risk of misinterpretation of peak CRF values in children. Using a moving average approach decreased misinterpretation and increased accuracy.

Inhaled Epoprostenol for Pulmonary Hypertension Treatment in Neonates: A 12-Year Experience.

BACKGROUND: Persistent pulmonary hypertension of the newborn (PPHN) occurs in 10% of neonatal respiratory insufficiency. To selectively reduce pulmonary vascular resistance, several treatments have been tried. Inhaled epoprostenol (iPGI2) has been used for 12 years in our institution for the management of refractory PPHN despite the gaps in the literature to support this use. OBJECTIVES: The primary objective was to evaluate the efficacy of iPGI2 for PPHN. The secondary objectives were to describe its use in neonates and assess side effects. STUDY DESIGN: This retrospective cohort study included infants < 28 days with PPHN treated with iPGI2 in the neonatal or pediatric intensive care units of our institution between 2004 and 2016. RESULTS: We reviewed 43 patient' care episodes (mean gestational age of 36 weeks). This was an extremely ill population with 54% mortality rate. Oxygenation index improved significantly after 12-hour treatment (p = 0.047), with a rebound effect when discontinuing nebulization. By the end of the therapy, the fraction of inspired oxygen had significantly dropped (p = 0.0018). Echocardiographic markers tended to normalize during treatment. No potential side effects were reported. CONCLUSION: In these sick newborns, we observed an improvement in PPHN under iPGI2 without significant adverse effects. To our knowledge, this is the largest neonatal cohort reported to have received iPGI2 for PPHN.

Prevalence of left ventricle non-compaction criteria in adult patients with bicuspid aortic valve versus healthy control subjects.

Objective: The aim of this study was to compare the prevalence of left ventricle non-compaction (LVNC) criteria (or hypertrabeculation) in a cohort of patients with bicuspid aortic valve (BAV) and healthy control subjects (CTL) without cardiovascular disease using cardiovascular MR (CMR). Methods: 79 patients with BAV and 85 CTL with tricuspid aortic valve and free of known cardiovascular disease underwent CMR to evaluate the presence of LVNC criteria. The left ventricle was assessed at end-systole and end-diastole, in the short-axis, two-chamber and four-chamber views and divided into the 16 standardised myocardial segments. LVNC was assessed using the non-compacted/compacted (NC/C) myocardium ratio and was considered to be present if at least one of the myocardial segments had a NC/C ratio superior to the cut-off values defined in previous studies: Jenni et al (>2.0 end-systole); Petersen et al (>2.3 end-diastole); or Fazio et al (>2.5 end-diastole). Results: 15 CTL (17.6%) vs 8 BAV (10.1%) fulfilled Jenni et al's criterion; 69 CTL (81.2%) vs 49 BAV (62.0%) fulfilled Petersen et al's criterion; and 66 CTL (77.6%) vs 43 BAV (54.4%) fulfilled Fazio et al's criterion. Petersen et al and Fazio et al's LVNC criteria were met more often by CTL (p=0.006 and p=0.002, respectively) than patients with BAV, whereas this difference was not statistically significant according to Jenni et al's criterion (p=0.17). In multivariable analyses, after adjusting for age, sex, the presence of significant valve dysfunction (>mild stenosis or >mild regurgitation), indexed LV mass, indexed LV end-diastolic volume and LV ejection fraction, BAV was not associated with any of the three LVNC criteria. Conclusion: Patients with BAV do not harbour more LVNC than the general population and there is no evidence that they are at higher risk for the development of LVNC cardiomyopathy.

New Reference Values for Cardiopulmonary Exercise Testing in Children.

INTRODUCTION: Cardiopulmonary exercise testing is an essential tool to assess cardiorespiratory fitness (CRF) in children. There is a paucity of adequate pediatric reference values that are independent of body size and pubertal stage. The purpose of this study is to provide Z score equations for several maximal and submaximal CRF parameters derived from a prospectively recruited sample of healthy children. METHODS: In this cross-sectional multicenter study, we prospectively recruited 228 healthy children 12 to 17 yr old in local schools. We performed a symptom-limited cardiopulmonary exercise testing progressive ramp protocol on an electronically braked cycle ergometer. Eighteen CRF parameters were analyzed. We tested several regression models to obtain prediction curves that minimized residual association with age, body size, and pubertal stage. Both the predicted mean and the predicted SD were modeled to account for heteroscedasticity. RESULTS: We identified nonlinear association of CRF parameters with body size and significant heteroscedasticity. To normalize CRF parameters, the use of a single body size variable was not sufficient. We therefore used multivariable models with various combination of height, corrected body mass, and age. Final prediction models yielded adjusted CRF parameters that were independent of age, sex, body mass, height, body mass index, and Tanner stages. CONCLUSIONS: We present Z score equations for several CRF parameters derived from a healthy pediatric population. These reference values provide updated predicted means and range of normality that are independent of sex and body size. Further testing is needed to assess if these reference values increase sensitivity and specificity to identify abnormal cardiorespiratory response in children with chronic diseases.

Thrombolysis of prosthetic mitral valve thrombosis in an infant.

A 7-week-old female developed thrombosis of a mechanical mitral valve and was successfully treated with recombinant tissue plasminogen activator (rt-PA). The management of infants with thrombosed mechanical prosthesis is reviewed.

Effect of age and aortic valve anatomy on calcification and haemodynamic severity of aortic stenosis.

OBJECTIVE: To evaluate the effect of age and aortic valve anatomy (tricuspid (TAV) vs bicuspid (BAV) aortic valve) on the relationship between the aortic valve calcification (AVC) and the haemodynamic parameters of aortic stenosis (AS) severity. METHODS: Two hundred patients with AS and preserved left ventricular ejection fraction were prospectively recruited in the PROGRESSA (Metabolic Determinants of the Progression of Aortic Stenosis) study and underwent a comprehensive Doppler echocardiography and multidetector CT (MDCT). Mean transvalvular gradient (MG) measured by Doppler echocardiography was used to assess AS haemodynamic severity and AVC was evaluated by MDCT using the Agatston method and indexed to the left ventricular outflow tract area to obtain AVC density (AVCd). All analyses were adjusted for sex. RESULTS: Thirty-nine patients had a BAV and 161 a TAV. Median age was 51 and 72 years for BAV and TAV patients, respectively. There was a modest correlation between MG and AVCd (ρ=0.51, p<0.0001) in the whole cohort. After dichotomisation for valve anatomy, there was a good correlation between AVCd and MG in the TAV group (ρ=0.61, p<0.0001) but weak correlation in the BAV group (ρ=0.32, p=0.046). In the TAV group, the strength of the AVCd-MG correlation was similar in younger (<72 years old; ρ=0.59, p<0.0001) versus older (≥72 years old; ρ=0.61, p<0.0001) patients. In the BAV group, there was no correlation between AVCd and MG in younger patients (<51 years old; ρ=0.12, p=0.65), whereas there was a good correlation in older patients (≥51 years old; ρ=0.55, p=0.009). AVCd (p=0.005) and age (p=0.02) were both independent determinants of MG in BAV patients while AVCd (p<0.0001) was the only independent determinant of MG in TAV patients. CONCLUSIONS: In patients with TAV as well as in older patients with BAV, AVCd appears to be the main factor significantly associated with the haemodynamic severity of AS and so it may be used to corroborate AS severity in case of uncertain or discordant findings at echocardiography. However, among younger patients with BAV, some may have a haemodynamically significant stenosis with minimal AVCd. The results of MDCT AVCd should thus be interpreted cautiously in this subset of patients. TRIAL REGISTRATION NUMBER: NCT01679431; Pre-results.

Family Based Whole Exome Sequencing Reveals the Multifaceted Role of Notch Signaling in Congenital Heart Disease.

Left-ventricular outflow tract obstructions (LVOTO) encompass a wide spectrum of phenotypically heterogeneous heart malformations which frequently cluster in families. We performed family based whole-exome and targeted re-sequencing on 182 individuals from 51 families with multiple affected members. Central to our approach is the family unit which serves as a reference to identify causal genotype-phenotype correlations. Screening a multitude of 10 overlapping phenotypes revealed disease associated and co-segregating variants in 12 families. These rare or novel protein altering mutations cluster predominantly in genes (NOTCH1, ARHGAP31, MAML1, SMARCA4, JARID2, JAG1) along the Notch signaling cascade. This is in line with a significant enrichment (Wilcoxon, p< 0.05) of variants with a higher pathogenicity in the Notch signaling pathway in patients compared to controls. The significant enrichment of novel protein truncating and missense mutations in NOTCH1 highlights the allelic and phenotypic heterogeneity in our pediatric cohort. We identified novel co-segregating pathogenic mutations in NOTCH1 associated with left and right-sided cardiac malformations in three independent families with a total of 15 affected individuals. In summary, our results suggest that a small but highly pathogenic fraction of family specific mutations along the Notch cascade are a common cause of LVOTO.

Mutations in SGOL1 cause a novel cohesinopathy affecting heart and gut rhythm.

The pacemaking activity of specialized tissues in the heart and gut results in lifelong rhythmic contractions. Here we describe a new syndrome characterized by Chronic Atrial and Intestinal Dysrhythmia, termed CAID syndrome, in 16 French Canadians and 1 Swede. We show that a single shared homozygous founder mutation in SGOL1, a component of the cohesin complex, causes CAID syndrome. Cultured dermal fibroblasts from affected individuals showed accelerated cell cycle progression, a higher rate of senescence and enhanced activation of TGF-ß signaling. Karyotypes showed the typical railroad appearance of a centromeric cohesion defect. Tissues derived from affected individuals displayed pathological changes in both the enteric nervous system and smooth muscle. Morpholino-induced knockdown of sgol1 in zebrafish recapitulated the abnormalities seen in humans with CAID syndrome. Our findings identify CAID syndrome as a novel generalized dysrhythmia, suggesting a new role for SGOL1 and the cohesin complex in mediating the integrity of human cardiac and gut rhythm.

Rare copy number variants contribute to congenital left-sided heart disease.

Left-sided congenital heart disease (CHD) encompasses a spectrum of malformations that range from bicuspid aortic valve to hypoplastic left heart syndrome. It contributes significantly to infant mortality and has serious implications in adult cardiology. Although left-sided CHD is known to be highly heritable, the underlying genetic determinants are largely unidentified. In this study, we sought to determine the impact of structural genomic variation on left-sided CHD and compared multiplex families (464 individuals with 174 affecteds (37.5%) in 59 multiplex families and 8 trios) to 1,582 well-phenotyped controls. 73 unique inherited or de novo CNVs in 54 individuals were identified in the left-sided CHD cohort. After stringent filtering, our gene inventory reveals 25 new candidates for LS-CHD pathogenesis, such as SMC1A, MFAP4, and CTHRC1, and overlaps with several known syndromic loci. Conservative estimation examining the overlap of the prioritized gene content with CNVs present only in affected individuals in our cohort implies a strong effect for unique CNVs in at least 10% of left-sided CHD cases. Enrichment testing of gene content in all identified CNVs showed a significant association with angiogenesis. In this first family-based CNV study of left-sided CHD, we found that both co-segregating and de novo events associate with disease in a complex fashion at structural genomic level. Often viewed as an anatomically circumscript disease, a subset of left-sided CHD may in fact reflect more general genetic perturbations of angiogenesis and/or vascular biology.

Structure and process measures of quality of care in adult congenital heart disease patients: a pan-Canadian study.

BACKGROUND: There are more adults than children with congenital heart disease. Of over 96,000 ACHD patients in Canada, approximately 50% require ongoing expert care. In spite of published recommendations, data on the quality of care for ACHD patients are lacking. METHODS: Survey methodology targeted all Canadian Adult Congenital Heart (CACH) network affiliated ACHD centers. Clinics were asked to prospectively collect outpatient and procedural volumes for 2007. In 2008, centers were surveyed regarding infrastructure, staffing, patient volumes and waiting times. RESULTS: All 15 CACH network registered centers responded. The total number of patients followed in ACHD clinics was 21,879 (median per clinic=1132 (IQR: 585, 1816)). Of the total 80 adult and pediatric cardiologists affiliated to an ACHD clinic, only 27% had received formal ACHD training. Waiting times for non-urgent consultations were 4 ± 2 months, and 4 ± 3 months for percutaneous and surgical procedures. These were beyond Canadian recommended targets at 11 sites (73%) for non-urgent consultations, at 8 sites (53%) for percutaneous interventions and 13 sites (87%) for surgery. CONCLUSIONS: Of a minimum number of 96,000 ACHD patients in Canada, only 21,879 were being regularly followed in 2007. At most sites waiting times for ACHD services were beyond Canadian recommended targets. In spite of universal health care access, published guidelines for ACHD patient structure and process measures of health care quality are not being met.

Design and rationale of a genetic cohort study on congenital cardiac disease: experiences from a multi-institutional platform in Quebec.

BACKGROUND: Congenital cardiac disease is the most common malformation, and a substantial source of mortality and morbidity in children and young adults. A role for genetic factors is recognised for these malformations, but overall few predisposing loci have been identified. Here we report the rationale, design, and first results of a multi-institutional congenital cardiac disease cohort, assembled mainly from the French-Canadian population of the province of Quebec and centred on families with multiple affected members afflicted by cardiac malformations. METHODS: Families were recruited into the study, phenotyped and sampled for DNA in cardiology clinics over the first 3 years of enrolment. We performed segregation analysis and linkage simulations in the subgroup of families with left ventricular outflow tract obstruction (LVOTO). RESULTS: A total of 1603 participants from 300 families were recruited, with 169 out of 300 (56.3%) families having more than one affected member. For the LVOTO group, we estimate heritability to be 0.46-0.52 in our cohort. Simulation analysis demonstrated sufficient power to carry out linkage analyses, with an expected mean log-of-odds (LOD) score of 3.8 in 67 pedigrees with LVOTO. CONCLUSION: We show feasibility and usefulness of a population-based biobank for genetic investigations into the causes of congenital cardiac disease. Heritability of LVOTO is high and could be accounted for by multiple loci. This platform is ideally suited for multiple analysis approaches, including linkage analysis and novel gene sequencing approaches, and will allow to establish segregation of risk alleles at family and population levels.

Assessment of electronic health information system use and need in US adult congenital heart disease centers.

OBJECTIVES: Efforts to improve care for adult congenital heart disease (ACHD) patients necessitates collection of accurate, detailed, longitudinal data. We sought to document what electronic health record systems are currently available at ACHD centers and to assess national interest in a uniform ACHD-focused system. DESIGN: Directors of ACHD centers in the United States were invited to complete an online questionnaire regarding current health information systems at their institution both for general cardiology and for ACHD. Topics that were surveyed included utility and perceived limitations of currently available systems. The survey also assessed the level of interest in an ACHD-specific system, and its optimal functions. RESULTS: Thirty-four centers responded, representing both pediatric and adult institutions that care for patients with ACHD. Of these, 80% reported using a variety of commercially supported electronic medical record products, whereas only 50% employed an ACHD-specific noncommercial database to supplement their institutional system. Comparison of the two systems revealed that most clinical activities are pursued through the institutional electronic medical record system. Research and tracking of clinical activities were the primary uses of ACHD-specific systems, which have several noted limitations. Strong interest in an integrated ACHD-specific system was found among responders. CONCLUSIONS: There is both an unmet need and a strong interest in an ACHD-oriented electronic health record that could facilitate research, outcome tracking, quality assurance, and inter-institutional collaboration, all functions that are lacking in electronic health systems currently in use.

Incidence, timing, and predictive factors of new-onset migraine headache attack after transcatheter closure of atrial septal defect or patent foramen ovale.

The objectives of this study were to evaluate the incidence, predictive factors, and duration of migraine headache attack (MHA) after transcatheter atrial septal defect (ASD) or patent foramen ovale (PFO) closure. A total of 260 consecutive patients who underwent ASD or PFO closure in our center answered a structured headache questionnaire focused in 3 period times, including (1) at baseline (just before closure), (2) within the 3 months after ASD-PFO closure, and (3) at the last (median 27 months, range 6 to 80 months) follow-up. All questionnaires were evaluated by a neurologist who established the diagnosis of MHA with or without aura, according to International Headache Society criteria. The Amplatzer ASD or PFO device was used in 95% of the patients, and aspirin, for at least 6 months, was the antithrombotic treatment in 91% of the cases. A total of 185 patients (71%) had no history of MHA before ASD-PFO closure, and these constituted the study population (mean age 39 +/- 21 years). MHA occurred in 13 patients (7%) after ASD-PFO closure, with aura in 9 of them. MHA appeared after a median of 10 days (range 0.3 to 30 days) after the procedure and were still present at the last follow-up (23 +/- 17 months) in 9 patients (69%). The median number of MHA within the 3 months after the procedure was 4 per month (interquartile range 1 to 23), and decreased to 1 per month (interquartile range 0.3 to 1) at the latest follow-up (p = 0.03). Compared with the patients who did not develop MHA, patients with MHA after ASD-PFO closure were younger (26 +/- 16 vs 39 +/- 21 years; p = 0.02) and were more likely to have undergone ASD closure (100% vs 58%; p = 0.001). In the multivariate analysis, ASD closure was the only predictor of MHA occurrence after the procedure (odds ratio 7.7; 95% confidence interval 1.5 to 22; p = 0.01). In conclusion, MHA, mostly with aura, occurred in 7% of patients after transcatheter ASD-PFO closure and persisted in most of them after a mean follow-up of 2 years. ASD closure was the only independent predictor of MHA occurrence after the procedure. These results suggest that mechanisms other than device composition are involved in the occurrence of MHA in these cases.

Life-threatening hemoptysis following the Fontan procedure.

Two cases of life-threatening recurrent hemoptysis occurring 10 years after a Fontan operation are presented. Bleeding from aortopulmonary collateral vessels was responsible for this complication in both cases, and the importance of systematic selective angiography of all potential origins of such abnormal vessels, including those arising from the abdominal aorta, is highlighted. Although coil embolization of aortopulmonary collateral vessels is usually definitive, pulmonary lobectomy may be necessary. The present report demonstrates, for the first time, that rescue extracorporeal membrane oxygenation support can be used as a bridge to surgery in case of severe uncontrollable hemoptysis in such cases.