Non-invasive assessment of liver abnormalities in pediatric Fontan patients.

Liver abnormalities are well known among long-term survivors of Fontan palliation, which remains the definite surgery for complex congenital heart disease and single ventricle physiology. Pediatric data however are scarce. We assessed the prevalence and degree of liver abnormalities in pediatric Fontan patients through non-invasive investigations suitable for longitudinal follow-up. Thirty-five patients with a median age of 11.8 years (5.2-16.6) and median time since Fontan of 6 years (1.17-13.83) were studied. Each child underwent a blood test, liver Doppler ultrasound (US), and transient elastography (TE). Healthy children were used as controls for TE measurement. AST, ALT, γGT, and direct bilirubin were abnormal in respectively 12 (34%), 5 (14%), 24 (69%), and 7 (20%) patients, while platelet count was decreased in 7 (20%). Splenomegaly was present in 7 (20%) patients. Portal vein mean flow velocity was < 15 cm/s in 19 (54%) patients indicative of portal hypertension. Twenty-two patients (63%) showed inferior vena cava collapsibility index values below 17%, indicating venous congestion. Hepatic artery and superior mesenteric artery resistance index were inversely correlated with time post Fontan (p < 0.05). TE values in Fontan patients were significantly higher than controls, with a median of 12.6 versus 4.6 kPa (p < 0.001) and were already increased shortly after Fontan completion. Conclusion: Liver abnormalities are frequently observed in pediatric Fontan patients. The non-invasive investigations used were not able to confirm liver fibrosis or differentiate hepatic congestion from fibrosis. Based on our findings, we propose a prospective screening protocol with serial measurements of laboratory, (Doppler) US, and TE parameters. What is Known: • Hepatic dysfunction is a well-known consequence of the Fontan circulation. • The natural history of Fontan-associated liver disease in the pediatric age group remains unclear. What is New: • Liver abnormalities are frequently observed in pediatric Fontan patients; however, differentiating liver fibrosis and hepatic congestion with non-invasive investigations remains challenging. Sonographic Doppler measurements may improve our insight in both Fontan-associated liver disease development and the functioning of the Fontan circulation. • A prospective screening protocol is proposed to improve our ability to detect Fontan-associated liver disease early on and understand its natural history.

Ethical and practical dilemmas in cardiac transplantation in infants: a literature review.

The waiting time in infants for a cardiac transplant remains high, due to the scarcity of donors. Consequently, waiting list morbidity and mortality are higher than those in other age groups. Therefore, the decision to list a small infant for cardiac transplantation is seen as an ethical dilemma by most physicians. This review aims to describe outcomes, limitations, and ethical considerations in infant heart transplantation. We used Medline and Embase as data sources. We searched for publications on infant (< 1 year) heart transplantation, bridge-to-transplant and long-term outcomes, and waiting list characteristics from January 2009 to March 2021. Outcome after cardiac transplant in infants is better than that in older children (1-year survival 88%), and complications are less frequent (25% CAV, 10% PTLD). The bridge-to-transplant period in infants is associated with increased mortality (32%) and decreased transplantation rate (43%). This is mainly due to MCS complications or the limited MCS options (with 51% mortality in infancy). Outcomes are worse for infants with CHD or in need of ECMO-support.Conclusion: Infants listed for cardiac transplantation have a high morbidity and mortality, especially in the period between diagnosis and transplantation. For those who receive cardiac transplant, the outlook is encouraging. Unfortunately, despite growing experience in VAD, mortality in children < 10 kg and children with CHD remains high. After transplantation, patients carry a psychological burden and there is a probability of re-transplantation later in life, with decreased outcomes compared to primary transplantation. These considerations are seen as an important ethical dilemma in many centers, when considering cardiac transplantation in infants (< 1 year). What is Known: • For infants, waitlist mortality remains high. In the pediatric population, MCS reduces the waiting list mortality. What is New: • Outcomes after infant cardiac transplantation are better than other age groups; however, MCS options remain limited, with persistently high waiting list mortality. • Future developments in MCS and alternative options to reduce waiting list mortality such as ABO-incompatible transplantation and pulmonary artery banding are encouraging and will improve ethical decision-making when an infant is in need of a cardiac transplant.

Determinants of Physical Fitness in Children with Repaired Congenital Heart Disease.

The aim of this study was to determine factors associated with physical fitness (PF) in children who underwent surgery for congenital heart disease (CHD). Sixty-six children (7-14 years) who underwent surgery for ventricular septal defect (n = 19), transposition of great arteries (n = 22), coarctation of aorta (n = 10), and tetralogy of Fallot (n = 15) were included. All children performed PF tests: cardiorespiratory fitness, upper- and lower-limb muscle strength, speed, balance, and flexibility. Cardiac evaluation was done via echocardiography and cardiopulmonary exercise test. Factors related to child's characteristics, child's lifestyle, physical activity motivators/barriers, and parental factors were assessed. Linear regression analyses were conducted. The results showed no significant differences in physical activity (PA) level by CHD type. Boys had better cardiorespiratory fitness (difference = 1.86 ml/kg/min [0.51;3.22]) and were more physically active (difference = 19.40 min/day [8.14;30.66]), while girls had better flexibility (difference = - 3.60 cm [- 7.07;- 0.14]). Physical activity motivators showed an association with four out of six PF components: cardiorespiratory fitness, coefficient = 0.063 [0.01;0.11]; upper-limb muscle strength, coefficient = 0.076 [0.01;0.14]; lower-limb muscle strength, coefficient = 0.598 [0.07;1.13]; and speed, coefficient = 0.03 [0.01;0.05]. Age, sex, and motivators together reached a maximum adjusted R2 = 0.707 for upper-limb strength. Adding other possible determinants did not significantly increase the explained variance. Apart from age and sex as non-modifiable determinants, the main target which might improve fitness would be the introduction of an intervention which increases the motivation to be active.

Myhre syndrome: A first familial recurrence and broadening of the phenotypic spectrum.

Myhre syndrome is a rare multisystem connective tissue disorder, characterized by short stature, facial dysmorphology, variable intellectual disability, skeletal abnormalities, arthropathy, cardiopathy, laryngotracheal anomalies, and stiff skin. So far, all molecularly confirmed cases harbored a de novo heterozygous gain-of-function mutation in SMAD4, encoding the SMAD4 transducer protein required for both transforming growth factor-beta and bone morphogenic proteins signaling. We report on four novel patients (one female proband and her two affected children, and one male proband) with Myhre syndrome harboring the recurrent c.1486C>T (p.Arg496Cys) mutation in SMAD4. The female proband presented with a congenital heart defect, vertebral anomalies, and facial dysmorphic features. She developed severe tracheal stenosis requiring a total laryngectomy. With assisted reproductive treatment, she gave birth to two affected children. The second proband presented with visual impairment following lensectomy in childhood, short stature, brachydactyly, stiff skin, and decreased peripheral sensitivity. Transmission electron microscopy (TEM) of the dermis shows irregular elastin cores with globular deposits and almost absent surrounding microfibrils and suggests age-related increased collagen deposition. We report on the first familial case of Myhre syndrome and illustrate the variable clinical spectrum of the disorder. Despite the primarily fibrotic nature of the disease, TEM analysis mainly indicates elastic fiber anomalies.

Evaluation of cardiopulmonary exercise testing, heart function, and quality of life in children after allogenic hematopoietic stem cell transplantation.

BACKGROUND: Physical fitness is an important determinant of quality of life (QOL) after hematopoietic stem cell transplantation. Cardiac function can influence exercise performance. The aim of this study was to assess these factors and their interrelationship. PROCEDURE: Children underwent cardiopulmonary exercise testing (CPET) at least 1 year after hematopoietic stem cell transplantation (HSCT) and were compared with healthy controls. Systolic and diastolic heart function and left ventricle (LV) wall dimensions were measured. Health-related QOL (HR-QOL) was evaluated using PedsQL questionnaires. RESULTS: Forty-three patients performed CPET (26 boys, 13.6 ± 3.4 years, weight 45.5 ± 13.3 kg, length 152.9 ± 17.5 cm, body surface area 1.35 ± 0.28). HSCT patients had lower maximal oxygen consumption (VO2peak/kg, 34.7 ± 8.4 vs 46.3 ± 7.1 mL/kg/min, P < 0.001), shorter exercise duration (9.1 ± 2.5 vs 12.9 ± 2.6 min, P < 0.001), and lower maximal load (%Ppeak 70.8 ± 19.7 vs 102.4% ± 15.9%, P < 0.001). Echocardiography demonstrated decreased interventricular septal wall thickness (interventricular septum in diastole [IVSd] Z-value -0.64 ± 0.69, P < 0.001), and more systolic (11% of patients) and diastolic dysfunction (high E/E' Z-value 1.06 ± 1.13, P < 0.001). LV dilatation correlates with VO2max/kg (r = -0.364, P = 0.017). HR-QOL showed lower overall and emotional functioning scores (respectively, P = 0.016 and P = 0.001). Patients after anthracycline therapy have the lowest maximal exercise performance, but have no difference in QOL. Diminished exercise performance is not encountered as a QOL limitation. Total body irradiation influences the domain of psychosocial functioning. CONCLUSIONS: LV (systolic and diastolic) and right ventricle dysfunctions justify the need for thorough cardiac follow-up in children after HSCT. Lower physical fitness levels and lower HR-QOL emphasize the importance of CPET and fitness programs.

How to Size ASDs for Percutaneous Closure.

Percutaneous closure is the treatment of choice for secundum-type atrial septal defects (ASD). Balloon sizing (BS) has been the method of choice for deciding on device size. Improved 2D- and 3D-transesophageal echocardiographic (TEE) imaging challenged the necessity of BS. Balloon sizing was performed with two additional techniques to measure the stretched dimension of the ASD. The 1st method uses a stiff guide wire which stretches the ASD and 2D TEE. The second technique uses 3D TEE. Two hundred and thirty-six patients with minimum 1-year follow-up were enrolled. The population was classified into three groups: BS (group 1) n = 90, 2D-TEE (group 2) n = 87, and 3D-TEE (group 3) n = 59. All groups showed a distinct correlation between the maximum baseline dimensions and the device size (R = 0.821). The relative expansion rate did not differ between BS and 3D-TEE. Group 2 (2D-TEE) showed a significantly lower expansion rate. Procedural success and complications did not differ statistically between the 3 groups. 2D TEE sizing was the simplest method without loss of accuracy. 3D sizing offers the advantage of accurate and fast shape assessment, but resulted in more undersizing. Accurate sizing of ASDs with a floppy septum remains a challenge.

Early and late outcomes after surgical management of congenital vascular rings.

Persistent respiratory or feeding problems in children may be associated with a congenital vascular ring. Surgical management is fairly standardized, but long-term outcomes are not well described. This study aims to investigate clinical presentation, surgical treatment, and risk factors for early mortality and late outcome. Our database revealed 62 surgically treated vascular ring patients between 1993 and 2014. Double aortic arch was the most common diagnosis (53%). Median age at operation was 1 year. Symptoms were mainly respiratory (89%) and feeding problems (32%). Median extubation time and hospital stay were 4 h and 5 days. Mean follow-up was 7.8 ± 5.8 years. Early mortality was 8% and was related to anatomical diagnosis, concomitant anomalies, and a need for preoperative intubation. Freedom from residual symptoms at 1 and 6 months was 63 and 82%, respectively. Freedom from inhalation therapy at the last follow-up was 82% and was influenced by a type of vascular ring and preoperative ventilation. Dysphagia symptoms always disappeared. CONCLUSION: Surgical relief of tracheoesophageal compression is commonly effective in vascular ring anomalies. Respiratory symptoms necessitating chronic inhalation therapy only persist in a minority of children. Patients with double aortic arch are at increased risk to remain symptomatic, particularly with infectious exacerbations.

Outcome after prenatal and postnatal diagnosis of complex congenital heart defects and the influence of genetic anomalies.

OBJECTIVE: Determine prenatal detection rate, mortality and association with genetic abnormalities in patients with severe CHD. METHOD: Single center retrospective study in patients with severe CHD diagnosed prenatally or postnatally (2006 to 2014). RESULTS: A total of 567 patients were included, 176 (31%) after prenatal diagnosis, with large differences in prenatal detection rate among CHD types. Coarctation (24%), tetralogy of Fallot (21%) and univentricular heart (19%) were the most prevalent CHD. Overall mortality rate was 30% with important contributions of prenatal mortality including termination of pregnancy (40%) and postnatal compassionate care (15%). In the group requiring surgery, mortality rate was 12%. Genetic testing was available in 70%. A genetic cause was present in 140/394 patients tested (36%; 25% in the total group). Mortality was higher in the group with abnormal genetic testing compared with those with normal or no genetic testing (57/141 vs 112/423; p = 0,002). CONCLUSION: Only one third of severe CHD are detected; overall mortality remains high (30%) with major contributions of termination of pregnancy and compassionate care. A genetic cause was found in 36% and was associated with a decreased survival. Counseling must include the possibility of associated genetic pathology and its impact on survival. © 2017 John Wiley & Sons, Ltd.

An Alternative Strategy for Bridge-to-Transplant/Recovery in Small Children with Dilated Cardiomyopathy.

Dilated cardiomyopathy in children still has a poor prognosis with high rates of mortality and cardiac transplantation (resp. around 20 and 25%). Awaiting transplantation or possible recovery, these pediatric patients are mechanically supported with extracorporeal membrane oxygenation or a paracorporeal ventricular assist device, both resulting in higher survival rates but also entailing considerable risks of infection, thrombosis, or bleeding. A new indication for an old technique, i.e., pulmonary artery banding, presents itself as an interesting alternative to mechanical circulatory support in selected infants and small children with dilated LV cardiomyopathy and preserved RV function. Here we present a brief review of literature and report on two patients in whom PAB has been successfully implemented as either bridge-to-recovery or bridge-to-transplant.

Current outcomes of the bi-directional cavopulmonary anastomosis in single ventricle patients: analysis of risk factors for morbidity and mortality, and suitability for Fontan completion.

OBJECTIVES: The bi-directional cavopulmonary anastomosis forms an essential staging procedure for univentricular hearts. This review aims to identify risk factors for morbidity, mortality, and suitability for Fontan completion. METHODS: A total of 114 patients undergoing cavopulmonary anastomosis between 1992 and 2012 were reviewed to assess primary - mortality and survival to Fontan completion - and secondary outcome endpoints - re-intubation, new drain, and ICU stay. Median age and weight were 8 months and 6.9 kg, respectively. In 83% of patients, 1-3 interventions had preceded. Norwood-type procedures became more prevalent over time. RESULTS: Extubation occurred after a median of 4 hours, median ICU stay was 2 days; 10 patients (8.8%) needed re-intubation and 18 received a new drain. Higher central venous pressure and transpulmonary gradient were risk factors for new drain insertion (p<0.01). Higher pre-operative pulmonary pressure correlated with increased inotropic support and prolonged intubation (p=0.01). Need for re-intubation was significantly affected by younger age at operation (p=0.01). Hospital and pre-Fontan mortality were 11.4 and 5.3%, respectively. Operative mortality was independently affected by younger age (p=0.013), lower weight (p=0.02), longer bypass time (p=0.04), and re-intubation (p=0.004). Interstage mortality was mainly influenced by moderate ventricular function (p=0.03); 82% of survivors underwent or are candidates for Fontan completion. CONCLUSION: The cavopulmonary anastomosis remains associated with adverse outcomes. Age at operation decreases with rising prevalence of complex univentricular hearts. Considering the important impact of re-intubation on hospital mortality, peri-operative management should focus on optimising cardio-respiratory status. Once this selection step is taken, successful Fontan completion can be expected, provided that ventricular function is maintained.

The Impact of Oral Intake of Dydrogesterone on Fetal Heart Development During Early Pregnancy.

Congenital heart disease is the most frequent form of congenital anomaly in newborn infants and accounts for more than a quarter of all serious congenital afflictions worldwide. A genetic etiology is identified in <20 % of cases of congenital heart defects, and in most cases the etiology remains a mystery. In the context of the health burden caused by congenital heart disease, the contribution of non-inherited risk factors is important especially if it turns out to be caused by a drug which can be avoided during pregnancy. We sought to determine whether maternal dydrogesterone treatment in early pregnancy is associated with congenital heart disease in the infant. We conducted a retrospective case-control study of birth defects and associated risk factors. Data were obtained and compared between 202 children born with congenital heart disease and a control group consisting of 200 children. All children were born in the period of 2010-2013. Dydrogesterone exposure was defined as any reported use during the first trimester of pregnancy. Exclusion criteria included stillbirths, children with chromosomal abnormalities and infants of mothers with chronic medical illnesses, e.g., diabetes. Binary logistic regression analyses were used to analyze the data and attempt to identify a causal relationship between drug exposure and congenital heart disease. Mothers of children born with congenital heart disease received more dydrogesterone during first trimester of pregnancy than mothers of children in the control group [adjusted odds ratio 2.71; (95 % CI 1.54-4.24); P = 0.001]. We identified a positive association between dydrogesterone usage during early pregnancy and congenital heart disease in the offspring. Nevertheless, further studies are needed to confirm these results.

Evaluation of a nurse-led multi-component transition program for adolescents with congenital heart disease.

OBJECTIVE: To evaluate the effectiveness of the transition program for adolescents with congenital heart disease (CHD) 'Transition With a Heart' (TWAH) on disease-related knowledge, quality of life (QoL), transition experiences, and gaps in follow-up. METHODS: A study with pre-posttest and control group (post-test) using consecutive sampling, including adolescents with moderate to severely complex CHD, without intellectual disability, aged≥ 12 y, and parents. After weighting, t-tests were performed. A multivariable regression analysis explored the outcomes' determinants. RESULTS: In the intervention group, 28 adolescents and 25 parents were included, and 53 adolescents and 18 parents as controls. Adolescents' knowledge significantly increased after completing TWAH (from 59.8% to 75.7%;p < 0.01). Their knowledge was positively correlated with TWAH (ß = +13.3;p < 0.01). Adolescents' transition experiences were also positively related to TWAH (general experience: ß = +5.5;p < 0.01; transfer satisfaction: ß = +0.8; p < 0.01). Adolescents' QoL was mainly determined by CHD complexity and not by TWAH. No one showed gaps in follow-up. TWAH was not associated with parents' transition experiences. CONCLUSION: Implementing TWAH substantially improved adolescents' disease-related knowledge and transition experiences. PRACTICE IMPLICATIONS: The results regarding transition experiences need to be confirmed by further research. The TWAH design with the person-tailored educational program, skills training, and the transition coordinator can be used in settings with other chronic diseases.

Multimodality 3D image fusion with live fluoroscopy reduces radiation dose during catheterization of congenital heart defects.

Introduction: Imaging fusion technology is promising as it is radiation and contrast sparing. Herein, we compare conventional biplane angiography to multimodality image fusion with live fluoroscopy using two-dimensional (2D)-three-dimensional (3D) registration (MMIF2D-3D) and assess MMIF2D-3D impact on radiation exposure and contrast volume during cardiac catheterization of patients with congenital heart disease (CHD). Methods: We matched institutional MMIF2D-3D procedures and controls according to patient characteristics (body mass index, age, and gender) and the seven procedure-type subgroups. Then, we matched the number of tests and controls per subgroup using chronological ordering or propensity score matching. Subsequently, we combined the matched subgroups into larger subgroups of similar procedure type, keeping subgroups with at least 10 test and 10 control cases. Air kerma (AK) and dose area product (DAP) were normalized by body weight (BW), product of body weight and fluoroscopy time (BW × FT), or product of body weight and number of frames (BW × FR), and stratified by acquisition plane and irradiation event type (fluoroscopy or acquisition). Three senior interventionists evaluated the relevance of MMIF2D-3D (5-point Likert scale). Results: The Overall group consisted of 54 MMIF2D-3D cases. The combined and matched subgroups were pulmonary artery stenting (StentPUL), aorta angioplasty (PlastyAO), pulmonary artery angioplasty (PlastyPUL), or a combination of the latter two (Plasty). The FT of the lateral plane reduced significantly by 69.6% for the Overall MMIF2D-3D population. AKBW and DAPBW decreased, respectively, by 43.9% and 39.3% (Overall group), 49.3% and 54.9% (PlastyAO), and 36.7% and 44.4% for the Plasty subgroup. All the aforementioned reductions were statistically significant except for DAPBW in the Overall and Plasty (sub)groups. The decrease of AKBW and DAPBW in the StentPUL and PlastyPUL subgroups was not statistically significant. The decrease in the median values of the weight-normalized contrast volume (CMCBW) in all five subgroups was not significant. Cardiologists considered MMIF2D-3D very useful with a median score of 4. Conclusion: In our institution, MMIF2D-3D overall enabled significant AKBW reduction during the catheterization of CHD patients and was mainly driven by reduced FT in the lateral plane. We observed significant AKBW reduction in the Plasty and PlastyAO subgroups and DAPBW reduction in the PlastyAO subgroup. However, the decrease in CMCBW was not significant.

Long-term follow-up of atrioventricular valve function in Fontan patients: effect of atrioventricular valve surgery.

OBJECTIVES: The aim of this study was to evaluate the relationship between atrioventricular valve and ventricular function in Fontan survivors, including the effect of atrioventricular valve surgery. METHODS: Analysis focused on transplant-free survival and the need for atrioventricular valve surgery in single ventricle patients after Fontan completion. Longitudinal echocardiographic examination of long-term valve and ventricular function was performed. RESULTS: Fontan completion was performed in 113 patients, having a right univentricular morphology in 33.6%, a left ventricle morphology in 62.8% and ambiguous in 3.6%. Perioperative mortality was 2.7% (n = 3). Within a median follow-up of 16.3 years (interquartile range 10.6-23.6), transplant-free survival was 96.1 ± 1.9% and 90.4 ± 5.8% at 10-25 years. Twenty AV valve procedures were performed in 14 (12.4%) children, respectively, pre-Fontan (n = 10), per-Fontan (n = 8) and post-Fontan (n = 2), resulting in a cumulative incidence of AV valve surgery is 5.7 ± 2.2% and 12.3 ± 3.2% at 1-5 years. Atrio-ventricular valve function deteriorated over time [hazard ratio (HR) 1.112, 95% confidence interval (CI) 1.089-1.138, P < 0.001], without difference for valve morphology (P = 0.736) or ventricular dominance (P = 0.484). AV valve dysfunction was greater in patients requiring AV valve surgery (HR 20.383, 95% CI 6.223-36.762, P < 0.001) but showed a comparable evolution since repair to those without valve surgery (HR 1.070, 95% CI 0.987-1.160, P = 0.099). Progressive time-related ventricular dysfunction was observed (HR 1.141, 95% CI 1.097-1.182, P < 0.001), significantly less in left ventricle-dominance (HR 0.927, 95% CI 0.860-0.999, P = 0.047) but more after AV valve surgery (HR 1.103, 95% CI 1.014-1.167, P = 0.022). CONCLUSIONS: In a homogeneously treated Fontan population, 25-year transplant-free survival is encouraging. Atrio-ventricular valve surgery was necessary in 12.4%, resulting mostly in a durable valve function. However, a slow time-related decline of atrioventricular valve function as of ventricular function is worrisome, evoking a role for additional heart failure therapy.

Pulmonary artery banding as adjunct therapy for ventricular recovery after anomalous left coronary artery from the pulmonary artery repair: a case report.

Anomalous left coronary artery from the pulmonary artery is a rare congenital coronary anomaly commonly associated with severe but reversible left ventricular dysfunction. We present an anomalous left coronary artery from the pulmonary artery case of persisting left ventricular failure with inability to wean off the ventilator and inotropes after successful coronary reimplantation, in whom pulmonary artery banding enhanced myocardial recovery.

Hypertension after coarctation repair-a systematic review.

Background: Coarctation of the Aorta (CoA) leads to increased morbidity and mortality later in life despite early surgical or percutaneous treatment. Many long-term complications are related to hypertension (HT) which is a common finding late after coarctation repair. Methods: A systematic Review was performed including articles published between February 2012 to December 2020. Systematic searches were conducted on PubMed and the Cochrane Controlled Trials Register to look for studies on HT after aortic CoA-repair. PRISMA guidelines were used. Results: In this systematic review on HT after CoA Repair the mean prevalence of HT was 47.3% (20-70%). A progressive character was of the HT was found, furthermore if only studies are included with 24 h blood pressure (BP) recording in addition to standard BP measurements, the incidence of HT rose to 57.8%. Discussion: Most clinical studies look at complications, mortality rate and residual pressure gradient rather than correlating hemodynamic indices with long-term outcome. Although HT is commonly based in measurement of peripheral BP, it has been shown that peripheral BP in CoA patients has a poor correlation with central aortic pressure. Central aortic hemodynamics are significantly altered in patients with repaired CoA, which can now adequately be investigated non-invasively. At the present time there are no studies linking long-term outcome with abnormal central hemodynamics.

Exploring the Mutational Landscape of Isolated Congenital Heart Defects: An Exome Sequencing Study Using Cardiac DNA.

Congenital heart defects (CHD) are the most common congenital anomalies in liveborn children. In contrast to syndromic CHD (SCHD), the genetic basis of isolated CHD (ICHD) is complex, and the underlying pathogenic mechanisms appear intricate and are incompletely understood. Next to rare Mendelian conditions, somatic mosaicism or a complex multifactorial genetic architecture are assumed for most ICHD. We performed exome sequencing (ES) in 73 parent-offspring ICHD trios using proband DNA extracted from cardiac tissue. We identified six germline de novo variants and 625 germline rare inherited variants with 'damaging' in silico predictions in cardiac-relevant genes expressed in the developing human heart. There were no CHD-relevant somatic variants. Transmission disequilibrium testing (TDT) and association testing (AT) yielded no statistically significant results, except for the AT of missense variants in cilia genes. Somatic mutations are not a common cause of ICHD. Rare de novo and inherited protein-damaging variants may contribute to ICHD, possibly as part of an oligogenic or polygenic disease model. TDT and AT failed to provide informative results, likely due to the lack of power, but provided a framework for future studies in larger cohorts. Overall, the diagnostic value of ES on cardiac tissue is limited in individual ICHD cases.

Paediatric subaortic stenosis: long-term outcome and risk factors for reoperation.

OBJECTIVES: Surgical repair of subaortic stenosis (SAS) is associated with a substantial reoperation risk. We aimed to identify risk factors for reintervention in relation to discrete and tunnel-type SAS morphology. METHODS: Single-centre retrospective study of paediatric SAS diagnosed between 1992 and 2017. Multivariable Cox regression analysis was performed to identify reintervention risk factors. RESULTS: Eighty-five children [median age 2.5 (0.7-6.5) years at diagnosis] with a median follow-up of 10.1 (5.5-16.4) years were included. Surgery was executed in 83% (n = 71). Freedom from reoperation was 88 ± 5% at 5 years and 82 ± 6% at 10 years for discrete SAS, compared to, respectively, 33 ± 16% and 17 ± 14% for tunnel-type SAS (log-rank P < 0.001). Independent risk factors for reintervention were a postoperative gradient >20 mmHg [hazard ratio (HR) 6.56, 95% confidence interval (CI) 1.41-24.1; P = 0.005], tunnel-type SAS (HR 7.46, 95% CI 2.48-22.49; P < 0.001), aortic annulus z-score <-2 (HR 11.07, 95% CI 3.03-40.47; P < 0.001) and age at intervention <2 years (HR 3.24, 95% CI 1.09-9.86; P = 0.035). Addition of septal myectomy at initial intervention was not associated with lesser reintervention. Fourteen children with a lower left ventricular outflow tract (LVOT) gradient (P < 0.001) and older age at diagnosis (P = 0.024) were followed expectatively. CONCLUSIONS: Children with SAS remain at risk for reintervention, despite initially effective LVOT relief. Regardless of SAS morphology, age <2 years at first intervention, a postoperative gradient >20 mmHg and presence of a hypoplastic aortic annulus are independent risk factors for reintervention. More extensive LVOT surgery might be considered at an earlier stage in these children. SAS presenting in older children with a low LVOT gradient at diagnosis shows little progression, justifying an expectative approach.

A Reassessment of Copy Number Variations in Congenital Heart Defects: Picturing the Whole Genome.

Copy number variations (CNVs) can modulate phenotypes by affecting protein-coding sequences directly or through interference of gene expression. Recent studies in cancer and limb defects pinpointed the relevance of non-coding gene regulatory elements such as long non-coding RNAs (lncRNAs) and topologically associated domain (TAD)-related gene-enhancer interactions. The contribution of such non-coding elements is largely unexplored in congenital heart defects (CHD). We performed a retrospective analysis of CNVs reported in a cohort of 270 CHD patients. We reviewed the diagnostic yield of pathogenic CNVs, and performed a comprehensive reassessment of 138 CNVs of unknown significance (CNV-US), evaluating protein-coding genes, lncRNA genes, and potential interferences with TAD-related gene-enhancer interactions. Fifty-two of the 138 CNV-US may relate to CHD, revealing three candidate CHD regions, 19 candidate CHD genes, 80 lncRNA genes of interest, and six potentially CHD-related TAD interferences. Our study thus indicates a potential relevance of non-coding gene regulatory elements in CNV-related CHD pathogenesis. Shortcomings in our current knowledge on genomic variation call for continuous reporting of CNV-US in international databases, careful patient counseling, and additional functional studies to confirm these preliminary findings.

Pulmonary function in children after surgical and percutaneous closure of atrial septal defect.

This study aimed to study differences in lung function after surgical and percutaneous atrial septal defect (ASD) closure. Several studies have demonstrated abnormalities of pulmonary function in adults and children with ASD. These abnormalities persist even a few years after correction. This study compared pulmonary function between patients who underwent ASD closure by surgery and those who had closure by device. This is the ideal pediatric population for studying changes in lung function caused by cardiopulmonary bypass or sternotomy. The 46 patients in this study were treated by percutaneous closure (group 1) or surgical closure (group 2) of ASD and then scheduled for pulmonary function testing an average of 5.8 years after ASD closure. The mean values of functional residual capacity, total lung capacity, and residual volume did not differ between the two groups. The surgical group showed a significant decrease in expiratory reserve volume (p < 0.04) and forced vital capacity (p < 0.03). Expiratory flow at 25, 50, and 75% of forced vital capacity did not differ between the two groups but was on the lower limit of normal in both groups. Percutaneous closure of ASD can minimize the side effects of surgical closure on lung function. Longitudinal lung function follow-up assessment after cardiac surgery is warranted to detect and measure restrictive abnormalities in this type of congenital heart disease and others.