Conotruncal Defects Research Articles

Risk of venous thromboembolism in patients with congenital heart disease: a nationwide, register-based, case-control study.

Patients with congenital heart disease (CHD) have an increased risk of developing acquired cardiovascular diseases. However, the risk of venous thromboembolism (VTE) in patients with CHD is unknown. We aimed to investigate the incidence and risk of VTE in patients with CHD compared with matched controls without CHD. Data from Swedish health registers were used to identify all patients with CHD between 1970 and 2017 in Sweden. Each patient with CHD was matched with 10 controls from the Swedish Total Population Register. The primary outcome of the study was an event of VTE. Follow-up was from birth until VTE, death, or the end of the study (2017). Cox proportional hazard models were used to investigate the risk of VTE in patients with CHD and controls. A total of 67 814 patients with CHD and 583 709 matched controls were identified and included in the study. During a mean follow-up of 15.9 (SD ± 12.5) years, 554 (0.8%) patients with CHD and 1571 (0.3%) controls developed VTE. The risk of VTE was 3.3 [95% confidence interval [CI] 2.6-3.4) times higher in patients with CHD than in controls. Patients with conotruncal defects had the highest risk of VTE (hazard ratio 7.06, 95% CI 5.52-9.03). In our nationwide study, we found that the risk of VTE in patients with CHD was more than three times higher than in matched controls. The highest risk of VTE was in patients with the most complex lesions. Further research is crucial to clarify the underlying risk factors and prevent VTE in patients with CHD.

Prenatal chromosomal microarray analysis in a large Chinese cohort of fetuses with congenital heart defects: a single center study

Background and objectivesCongenital heart defect (CHD) is one of the most common birth defects. The aim of this cohort study was to evaluate the prevalence of chromosomal abnormalities and the clinical utility of chromosomal microarray analysis (CMA) in fetuses with different types of CHD, aiming to assist genetic counseling and clinical decision-making.MethodsIn this study, 642 fetuses with CHD were enrolled from a single center over a six-year period (2017–2022). Both conventional karyotyping and CMA were performed simultaneously on these fetuses.ResultsThe diagnostic yield of CMA in fetuses with CHD in our study was 15.3% (98/642). Our findings revealed a significant increase in the diagnostic yield of CMA compared to karyotyping in fetuses with CHD. Among CHD subgroups, the diagnostic yields were high in complex CHD (34.9%), conotruncal defects (28.6%), right ventricular outflow tract obstructive defects (RVOTO) (25.9%), atrioventricular septal defects (AVSD) (25.0%) and left ventricular outflow tract obstructive defects (LVOTO) (24.1%), while those in other CHD (10.6%) and septal defects (10.9%) were relatively low. The overall detection rate of clinically significant chromosomal abnormalities was significantly higher in the non-isolated CHD group compared to the isolated CHD group (33.1% vs. 9.9%, P < 0.0001). Interestingly, numerical chromosomal abnormalities were more likely to occur in the non-isolated CHD group than in the isolated CHD group (20.3% vs. 2.0%, P < 0.0001). The rate of termination of pregnancy (TOP)/Still birth in the non-isolated CHD group was significantly higher than that in the isolated CHD group (40.5% vs. 20.6%, P < 0.0001). Compared to the isolated CHD group, the detection rate of clinically significant chromosomal abnormalities was significantly higher in the group of CHD with soft markers (35.6% vs. 9.9%, P < 0.0001) and in the group of CHD with additional structural anomalies (36.1% vs. 9.9%, P < 0.0001).ConclusionsCMA is a reliable and high-resolution technique that should be recommended as the front-line test for prenatal diagnosis of fetuses with CHD. The prevalence of chromosomal abnormalities varies greatly among different subgroups of CHD, and special attention should be given to prenatal non-isolated cases of CHD, especially those accompanied by additional structural anomalies or soft markers.

Gata6 functions in zebrafish endoderm to regulate late differentiating arterial pole cardiogenesis.

Mutations in GATA6 are associated with congenital heart disease, most notably conotruncal structural defects. However, how GATA6 regulates cardiac morphology during embryogenesis is undefined. We used knockout and conditional mutant zebrafish alleles to investigate the spatiotemporal role of gata6 during cardiogenesis. Loss of gata6 specifically impacts atrioventricular valve formation and recruitment of epicardium, with a prominent loss of arterial pole cardiac cells, including those of the ventricle and outflow tract. However, there are no obvious defects in cardiac progenitor cell specification, proliferation or death. Conditional loss of gata6 starting at 24 h is sufficient to disrupt the addition of late differentiating cardiomyocytes at the arterial pole, with decreased expression levels of anterior secondary heart field (SHF) markers spry4 and mef2cb. Conditional loss of gata6 in the endoderm is sufficient to phenocopy the straight knockout, resulting in a significant loss of ventricular and outflow tract tissue. Exposure to a Dusp6 inhibitor largely rescues the loss of ventricular cells in gata6-/- larvae. Thus, gata6 functions in endoderm are mediated by FGF signaling to regulate the addition of anterior SHF progenitor derivatives during heart formation.

Assisted reproductive technology and the risk of fetal congenital heart disease: insights from a tertiary-care referral center

PurposeTo investigate whether congenital heart diseases exhibit higher rates in pregnancies achieved through assisted reproductive technology (ART) compared to natural conception.MethodsIn this retrospective cohort study, multinomial logistic regression was employed to analyze the relationship between categories of congenital heart diseases and three conception groups (IVF, ICSI, and natural pregnancies). The main outcome measures are risks of congenital heart disease categories in IVF and ICSI groups using the natural group as reference. We selected fetuses referred for fetal echocardiography to IRCCS Policlinico Sant’Orsola, Bologna, between January 2005 and November 2023, diagnosed with congenital heart diseases.ResultsWe categorized the congenital heart diseases into six groups based on anatomical and embryological criteria. The estimated risk of left ventricular outflow tract, valvular, conotruncal, and atrioventricular septal defects was lower in the IVF group compared to natural conception. The estimated risk of valvular and atrioventricular septal defects was lower in the ICSI group vs natural. Conversely, the risk for right heart anomalies was higher both in the IVF and ICSI groups compared to natural conception. Heart rhythm diseases were more frequent in IVF pregnancies. When comparing ART methods, valvular defects, conotruncal defects, and right heart anomalies were more frequently observed in the ICSI group, while atrioventricular septal defects were more common in the IVF group.ConclusionSignificant differences were found in the occurrence of congenital heart diseases in pregnancies conceived through IVF and ICSI, versus those conceived naturally, underscoring the importance of further studying the underlying mechanisms of these associations.

P-769 Congenital heart defects in children born after assisted reproductive technology: A large cohort study from the Committee of Nordic Assisted Reproductive Technology and Safety (CoNARTaS)

Abstract Study question Are children conceived after assisted reproductive technology (ART) more likely to be born with congenital heart defects (CHDs) than those born after spontaneous conception (SC)? Summary answer Major CHDs and severe CHDs are associated with ART, with a higher risk in both ART-conceived singletons and multiples compared to singletons from SC. What is known already Children born after ART have higher risk of birth defects compared to children born after SC. Among these defects, CHDs hold the highest prevalence, accounting for about 50% of all major birth defects and affecting approximately 1-2% of children in the general population. Several cohort studies and systematic reviews, among these a recent review including 41 studies and in total 25,856 ART children, shows increased risk of CHDs in children born after ART. However, conflicting findings have been reported for specific CHDs. Study design, size, duration This Nordic registry-based cohort study included 7,747,637 liveborn children, with 171,735 conceived after ART. All liveborn children (singletons and multiples) in Denmark (1994–2014), Finland (1990–2014), Norway (1984–2015), and Sweden (1987–2015) were included. National data from ART registries, medical birth registries, patient registries, cause of death registries, and population registries were cross-linked. Participants/materials, setting, methods The International Classification of Diseases (ICD) versions 8, 9, 10 were used for selection of CHDs. Major and severe CHDs were defined according to European Concerted Action on Congenital Anomalies and Twins (EUROCAT). Outcomes were major CHDs, severe CHDs, six hierarchical CHD lesion groups, and ten selected major CHDs. CHD diagnoses were considered prenatally or within the first year of life in Denmark, Finland, Sweden, and prenatally or at birth in Norway. Main results and the role of chance Major CHDs occurred among 1.84% (n = 3159) children born after ART and among 1.15% (n = 86,824) children born after SC, with adjusted odds ratio (AOR) 1.36; 95% CI 1.31–1.41. Risk was highest in multiples, regardless of conception method. Severe CHDs were detected in 0.35% (n = 594) children born after ART and in 0.26% (n = 19,375) children born after SC; AOR 1.30; 95% CI 1.20–1.42. When analysing the risk of CHD for the specific groups of CHDs by the hierarchical classification, children born after ART had higher risk of CHDs than children born after SC for five of the six lesion groups: conotruncal defects, non-conotruncal defects, ventricular septal defect, atrial septal defects, and other CHDs. ART was further associated with an elevated risk in four of ten selected major CHDs. Major CHDs occurred among 1.62% (n = 2059) singletons born after ART and among 1.11% (n = 18,539) singletons born after SC; AOR 1.19; 1.14–1.24. The prevalence of severe CHDs was 0.31% (n = 399) among singletons born after ART and 0.25% (n = 18,539) among singletons born after SC; AOR 1.20; 95% CI 1.09–1.33. In singletons born after ART, no difference was seen between ICSI and IVF or between frozen and fresh embryo transfer for major CHDs or severe CHDs. Limitations, reasons for caution A main limitation in this study is the lack of information on CHDs in miscarriages, pregnancy terminations, and stillbirths. Another limitation is that information on specific techniques used in assisted reproduction was not available from Finland. Lastly, we did not have information on causes of infertility. Wider implications of the findings CHDs, although rare, imply severe risks. Our study reveals an association between ART and major CHDs. While most CHD-affected children survive to adulthood, high morbidity and mortality rates persist in childhood and adulthood. The potential benefit of fetal echocardiography screening in ART pregnancies, beyond routine obstetric ultrasound, remains uncertain. Trial registration number ISRCTN 11780826

Impact of Appropriate Use Criteria for Cross-Sectional Imaging on Medical Decision-Making in Patients with Conotruncal Defects.

Associations between Appropriate Use Criteria (AUC) ratings and medical decision-making in congenital heart disease are not well-established. We applied the 2020 AUC for multimodality imaging in follow-up care of pediatric and young adult patients with conotruncal defects to evaluate appropriateness of cardiac magnetic resonance (CMR) and computed tomography (CCT) use in this population and impact on clinical decision-making. Records were reviewed and assigned AUC indications and corresponding ratings for CMR and CCT. We examined the relationship between AUC indications, their ratings, and change in management. Of the 200 studies (133 CMR, 67 CCT) performed on 187 patients, no studies were rated Rarely Appropriate (R), and most studies were obtained for routine follow-up (151/200 [75.5%]) and were not prompted by clinical concerns. There were 70/200 (35.0%) studies which led to management changes; these included transcatheter intervention (29/70 [41.4%]), surgical intervention (25/70 [35.7%]), other interventions (10/70 [14.3%]), and medical intervention (6/70 [8.6%]). Among all studies, studies prompted by clinical concerns and studies rated M more frequently resulted in change in management (46.9 vs 31.1%, p = 0.04 and 54.1 vs 30.7%, p = 0.003, respectively). In conclusion, we found that all studies were ordered for indications rated Appropriate (A) or May be Appropriate (M), indicating compliance in ordering practices as outlined by published AUC. Studies ordered for clinical change or rated M more frequently led to management change in patient care. Findings may help inform provider expectations of testing yield in this population and serve as a platform for development of future iterations of AUC.

Efficiency of copy number variation sequencing combined with karyotyping in fetuses with congenital heart disease and the following outcomes

BackgroundBoth copy number variant-sequencing (CNV-seq) and karyotype analysis have been used as powerful tools in the genetic aetiology of fetuses with congenital heart diseases (CHD). However, CNV-seq brings clinicians more confusions to interpret the detection results related to CHD with or without extracardiac abnormalities. Hence, we conducted this study to investigate the clinical value of CNV-seq in fetuses with CHD.ResultsA total of 167 patients with fetal CHD including 36 single CHD (sCHD), 41 compound CHD (cCHD) and 90 non-isolated CHD (niCHD) were recruited into the study. 28 cases (16.77%, 28/167) were revealed with chromosomal abnormalities at the level of karyotype. The pathogenic detection rate (DR) of CNV-seq (23.17%, 19/82) was higher than that of karyotyping (15.85%, 13/82) in 82 cases by CNV-seq and karyotyping simultaneously. The DR of pathogenic copy number variations (PCNVs) (31.43%) was higher in niCHD subgroup than that in sCHD and cCHD (9.52% and 23.08%). Conotruncal defect (CTD) was one of the most common heart malformations with the highest DR of PCNVs (50%) in 7 categories of CHD. In terms of all the pregnancy outcomes, 67 (40.12%) cases were terminated and 100 (59.88%) cases were live neonates. Only two among 34 cases with a pathogenic genetic result chose to continue the pregnancy.ConclusionsCNV-seq combined with karyotyping is a reliable and accurate prenatal technique for identifying pathogenic chromosomal abnormalities associated with fetal CHD with or without extracardiac abnormalities, which can assist clinicians to perform detailed genetic counselling with regard to the etiology and related outcomes of CHD.

Exposure to Endocrine-Disrupting Chemicals and Congenital Heart Diseases: The Pooled Results Based on the Current Evidence.

The relationships between maternal exposure to endocrine-disrupting chemicals (EDCs) and congenital heart diseases (CHD) are not elucidated yet. The exposure levels of EDCs are generally estimated based on self-reported questionnaires or occupational exposure evaluations in the literature. Therefore, a study based on epidemiological data from human biospecimens is required to provide stronger evidence between maternal exposure to EDC and CHD. Embase, Pubmed, Scopus, and the Cochrane Library databases were searched for related research which provided risk estimates regarding the relationships between maternal EDC exposure and CHD in human offspring. Baseline characteristics and outcomes of CHD were extracted from each included study. Odds ratios (ORs) with 95% confidence intervals (CIs) were pooled to calculate the overall estimates of CHD. Subgroup and meta-regression analyses were performed to identify the sources of heterogeneity. Bootstrapping techniques were used in analyses where several studies originated from a similar population. A total of seventeen studies were involved in the meta-analyses. Maternal EDC exposure was significantly related to CHD in offspring (OR 2.15; 95%CI 1.64 to 2.83). EDC exposure was significantly associated with septal defects (OR 2.34; 95%CI 1.77 to 3.10), conotruncal defects (OR 2.54; 95%CI 1.89 to 3.43), right ventricular outflow tract obstruction (OR 2.65; 95%CI 1.73 to 4.07), left ventricular outflow tract obstruction (OR 3.58; 95%CI 2.67 to 4.79), anomalous pulmonary venous return (OR 2.31; 95%CI 1.34 to 4.00), and other heart defects (OR 2.49; 95%CI 1.75 to 3.54). In addition, maternal exposure to heavy metals, which included lead (OR 2.19; 95%CI 1.29 to 3.71), cadmium (OR 1.81; 95%CI 1.28 to 2.56), mercury (OR 2.23; 95%CI 1.13 to 4.44), and manganese (OR 2.65; 95%CI 1.48 to 4.74), increased risks for CHD significantly. In conclusion, based on the latest evidence, maternal EDC exposure may increase CHD risks in human offspring, especially in heavy metal exposure conditions.

Diagnostic yield after next-generation sequencing in pediatric cardiovascular disease

Genetic testing with exome sequencing and genome sequencing is increasingly offered to infants and children with cardiovascular diseases. However, the rates of positive diagnoses after genetic testing within the different categories of cardiac disease and phenotypic subtypes of congenital heart disease (CHD) has been little studied. We report the diagnostic yield after next-generation sequencing in 500 patients with CHD from diverse population subgroups that were enrolled at three different sites in the Clinical Sequencing Evidence-Generating Research consortium. Patients were ascertained due to a primary cardiovascular issue comprising arrhythmia, cardiomyopathy and/or CHD and corresponding human phenotype ontology terms were selected to describe the cardiac and extracardiac findings. We examined the diagnostic yield for patients with arrhythmia, cardiomyopathy and/or CHD and phenotypic subtypes of CHD comprising conotruncal defects, heterotaxy, left ventricular outflow tract obstruction, septal defects, and ‘Other’ heart defects. We found a significant increase in the frequency of positive findings for patients who underwent genome sequencing compared to exome sequencing and for syndromic cardiac defects compared to isolated cardiac defects. We also found significantly higher diagnostic rates for patients who presented with isolated cardiomyopathy compared to isolated CHD. For patients with syndromic presentations who underwent genome sequencing, there were significant differences in the numbers of positive diagnoses for phenotypic subcategories of CHD, ranging from 31.7% for septal defects to 60% for Other. Despite variation in the diagnostic yield at each site, our results support genetic testing in pediatric patients with syndromic and isolated cardiovascular issues and in all subtypes of CHD.

Enlarged cavum septum pellucidum and small thymus as markers for 22q11.2 deletion syndrome.

Enlarged cavum septum pellucidum (CSP) and hypoplastic thymus are proposed extra-cardiac fetal markers for 22q11.2 deletion syndrome. We sought to determine if they were part of the fetal phenotype of our cohort of fetuses with 22q11.2 deletion syndrome. Case-control study of fetuses evaluated from 2016 to 2022. The study group included fetuses with laboratory confirmation of 22q11.2 deletion syndrome. The control group included pregnancies with conotruncal cardiac anomalies with normal microarray as well as structurally normal fetuses with normal microarray. The CSP and thymus were routinely measured during anatomical ultrasound in all patients at their initial visit at 27.1±4.7weeks. The CSP and thymus measurements were classified as abnormal if they were >95% or <5% for gestational age, respectively. The groups were compared using analysis of variance or Kruskal-Wallis for continuous variables and Fisher's exact test for categorical variables. Logistic regression was performed, and a Receiver Operating Characteristic (ROC) curve was constructed. We identified 47 fetuses with 22q11.2 deletion syndrome and compared them to 47 fetuses with conotruncal anomalies and normal microarray and 47 structurally normal fetuses with normal microarray. 51% (24/47) of fetuses with 22q11.2 deletion syndrome had an enlarged CSP compared to 6% (3/47) of fetuses with a conotruncal anomaly and normal microarray and none of the structurally normal fetuses (p<0.001). Of the fetuses with 22q11.2 deletion syndrome, 83% (39/47) had a hypoplastic or absent thymus compared to 9% (4/47) of the fetuses with a conotruncal anomaly and normal microarray and none of the structurally normal fetuses (p<0.001). 87% (41/47) of the fetuses with 22q11.2 deletion syndrome had conotruncal cardiac anomalies. Logistic regression revealed that both enlarged CSP and hypoplastic/absent thymus were associated with 22q11.2 deletion syndrome. The area under the ROC curve for the two markers was 0.94. An enlarged CSP and hypoplastic/absent thymus appear to be part of the fetal phenotype of 22q11.2 deletion syndrome. These markers are associated with conotruncal anomalies in the setting of 22q11.2 deletion syndrome but not in normal controls or fetuses with conotruncal defects and normal microarrays.

ЗНАЧЕНИЕ ИММУНОЛОГИЧЕСКОГО СКРИНИНГА В ПРОГНОЗИРОВАНИИ ИНФЕКЦИОННЫХ ОСЛОЖНЕНИЙ КАРДИОХИРУРГИИ

Incidence of infectious complications in children with congenital heart disease, especially with cyanotic and complex defects, is higher than in the population, which is associated with both hemodynamic and immune disorders. Various types of primary immunodeficiencies in congenital heart disease and the dependence of immune disorders on the morphology of the defect, the severity of circulatory failure and arterial hypoxemia are described. The importance of diagnosing immunological disorders is emphasized to reduce the risk of infectious complications of cardiac surgery, reduce mortality and improve the outcomes of surgical interventions for congenital heart disease. The prognostic value of immune disorders identified by the TREC/KREC method for infectious complications of cardiac surgery has not been studied. The purpose of this research was to assess the possibility of predicting infectious complications of cardiac surgery in children with congenital heart disease based on screening using the TREC/KREC method. Material and methods used: preoperatively, 200 children with congenital heart disease aged 3 days to 12 months old were examined. Instrumental and laboratory methods were used including immunological screening for TREC/KREC DNA. Results: 123 (62.4%) were diagnosed with “acyanotic” congenital heart disease, 74 (37.5%) with various cyanotic congenital heart diseases and 10 (5%) with congenital heart diseases with Down syndrome, Di George syndrome, Williams syndrome or multiple malformations. 184 (92%) underwent various cardiac surgical interventions. Violations of T-cell immunity according to preoperative TREC/KREC screening were observed in 23.5% of cases including in all children with syndromic forms of congenital heart disease, multiple malformations, and significantly more often in cyanotic congenital heart disease, conotruncal defects, and those admitted in critical conditions. Infectious complications of cardiac surgery were observed significantly more often in this group than in children with normal T-cell immunity (in 36% and 3.6%, respectively). Conclusion: the prognostic value of TREC/KREC screening for targeted preparation and postoperative management in order to prevent infectious complications of cardiac surgery has been confirmed.

Tetralogy of Fallot with an anomalous origin of right coronary artery from the pulmonary artery in a case of type i aortopulmonary window—A diagnostic challenge

&lt;p&gt;Aortopulmonary (AP) window is a conotruncal defect with an incidence of &amp;lt; 1% amongst congenital heart defects. It often occurs in association with other congenital cardiac defects. Coronary artery anomalies in association with the AP window are infrequent. An anomalous right coronary artery (RCA) from the pulmonary artery (ARCAPA) is an extremely rare entity with 0.002% incidence in the general population. To the best of our knowledge, the triad of Tetralogy of Fallot (TOF), ARCAPA and AP window is not yet reported in the literature.&lt;/p&gt;

The evolving genetic etiology of conotruncal anomalies.

To assess the diagnostic yield of genetic testing for antenatally detected conotruncal defects. This was a retrospective analysis of all antenatally detected cases of conotruncal anomalies over a 4-year period. Patients were offered antenatal and postnatal genetic testing including QF-PCR, microarray and exome sequencing (ES) antenatally or genome sequencing (GS) postnatally on a case-by-case basis. There were 301 cases included. Overall, there were pathogenic genetic findings in 27.6% of the cases tested (53/192). The commonest finding was 22q11.21 deletion (20/192 cases, 10.4%), followed by trisomy 21 (6/192, 3.1%). There were 249 cases of isolated conotruncal anomalies, of which 59.8% (149/249) had genetic testing and 22.8% (34/149) had pathogenic findings. ES/GS was performed in five cases with no pathogenic findings. There were 52 cases of non-isolated contruncal anomalies, of which 82.7% (43/52) had genetic testing. ES/GS was performed in 11 cases in this group and increased the yield of clinically significant diagnoses from 32.6% (14/43) to 44.2% (19/43). Genetic abnormalities are present in over one quarter of cases of antenatally detected conotruncal anomalies. The commonest abnormality is 22q11.21 deletion. Exome sequencing or genome sequencing leads to a significant increase in genetic diagnosis in non-isolated cases.

Comparison of definitive approaches for conotruncal defects following bidirectional Glenn procedure

BackgroundStaged repair is common for complex conotruncal defects, often involving bidirectional Glenn (BDG) procedure. Following the cavopulmonary shunt, both Fontan completion and biventricular conversion (BiVC) serve as definitive approaches. The...

Incidence of diabetes mellitus and effect on mortality in adults with congenital heart disease

BackgroundWorldwide, 1–2% of children are born with congenital heart disease (CHD) with 97% reaching adulthood. ObjectivesThis study aims to demonstrate the risk of diabetes in patients with CHD, and the influence of incident diabetes on mortality in CHD patients and controls. MethodsBy combining data from patient registries, the incidence of adult-onset diabetes registered at age 35 or older, and subsequent mortality risk were analysed in two successive birth cohorts (born in 1930–1959 and 1960–1983), by type of CHD lesion and sex, compared with population-based controls matched for sex and year of birth and followed until a maximum of 87 years of age. ResultsOut of 24,699 patients with CHD and 270,961 controls, 8.4% and 5.6%, respectively, were registered with a diagnosis of diabetes at the age of 35 or older, hazard ratio (HR) 1.47 (95% CI 1.40–1.54). The risk of diabetes was higher in the second birth cohort (HR of 1.74, 95% CI 1.54–1.95) and increased with complexity of CHD. After onset of DM, the total mortality among patients with CHD was 475 compared to 411/ 10,000 person-years among controls (HR 1.16, 95% CI 1.07–1.25). ConclusionsIn this nationwide cohort of patients with CHD and controls, the incidence of diabetes was almost 50% higher in patients with CHD, with higher risk in the most recent birth cohort and in those with conotruncal defects, with the combination of CHD and diabetes associated with a significantly increased mortality compared to diabetic controls.

Human Genetics of Tetralogy of Fallot and Double-Outlet Right Ventricle.

Tetralogy of Fallot (TOF) and double-outlet right ventricle (DORV) are conotruncal defects resulting from disturbances of the second heart field and the neural crest, which can occur as isolated malformations or as part of multiorgan syndromes. Their etiology is multifactorial and characterized by overlapping genetic causes. In this chapter, we present the different genetic alterations underlying the two diseases, which range from chromosomal abnormalities like aneuploidies and structural mutations to rare singlenucleotide variations affecting distinct genes. For example, mutations in the cardiac transcription factors NKX2-5, GATA4, and HAND2 have been identified in isolated TOF cases, while mutations of TBX5 and 22q11 deletion, leading to haploinsufficiency of TBX1, cause Holt-Oram and DiGeorge syndrome, respectively. Moreover, genes involved in signaling pathways, laterality determination, and epigenetic mechanisms have also been found mutated in TOF and/or DORV patients. Finally, genome-wide association studies identified common singlenucleotide polymorphisms associated with the risk for TOF.

Fever and antibiotic use in maternal urinary tract infections during pregnancy and risk of congenital heart defects: Findings from the National Birth Defects Prevention Study.

Previous studies report an association between prenatal maternal urinary tract infections (UTI) and specific congenital heart defects (CHDs); however, the role of fever and antibiotic use on this association is poorly understood. Using data from the National Birth Defects Prevention Study, we examined whether the relationship between maternal UTIs during the periconceptional period and occurrence of CHDs is modified by the presence of fever due to UTI and corresponding antibiotic use among 11,704 CHD case infants and 11,636 live-born control infants. Information on UTIs, fever associated with UTI and antibiotic use (sulfonamides, nitrofurantoin, cephalosporins, penicillin, macrolides, and quinolones) during pregnancy were obtained using a computer-assisted telephone interview. Using unconditional multivariable logistic regression, we calculated adjusted odds ratios (ORs) to determine the association between maternal UTIs and subtypes of CHDs. Analyses were stratified by the presence of fever and medication use associated with UTI. The prevalence of UTIs during the periconceptional period was 7.6% in control mothers, and 8.7% in case mothers. In the absence of fever, UTI was associated with secundum atrial septal defects (ASD) (OR 1.3; 95% confidence interval [CI] 1.1-1.5) and in the absence of antibiotics, UTI was associated with conotruncal defects as a group and for four specific CHDs. When fever and UTI occurred concomitantly, no significantly elevated odds ratios were noticed for any subtypes of CHD. Among women with UTIs who used antibiotics, an elevated but statistically non-significant estimate was observed for secundum ASD (OR 1.4; 95% CI 1.0-2.0). Findings in the present study suggest that fever due to UTI and corresponding maternal antibiotic use do not substantially modify the association between maternal UTIs and specific CHDs in offspring. Further studies with larger sample sizes are warranted to guide clinical management of UTIs during the periconceptional period.

Case report: A novel combination of anomalies in a patient with 22q11.2 deletion syndrome

A frequently occurring genetic disorder, 22q11.2 deletion syndrome can manifest with various abnormalities. The range of cardiac anomalies associated with this syndrome is extensive, with conotruncal defects being the most prevalent. In this study, we report the case of a patient with a unique combination of anatomical abnormalities such as crisscross pulmonary arteries, a cervical aortic arch with coarctation of the aorta, and a ventricular septal defect. The patient underwent initial surgical intervention, which resulted in significant clinical improvement.

Immunodeficiency Disorders in Congenital Heart Diseases (Review)

The study data of the last two decades on primary and secondary immunodeficiency in congenital heart defects (CHD) as a cause of frequent infectious complications before and after cardiac surgery are presented. Based on screenings of various levels, data are provided on the greater severity of immunological disorders in critical and cyanotic CHD in conotruncal defects compared with those in septal defects and stenotic defects. Violations were more often related to T-cell function and immunoglobulin deficiency (especially the IgG and IgG4 subgroups). Various types of primary immunodeficiency were found in 13 genetic syndromes in combination with CHD. The review discusses the possibility of using the technique of quantitative determination of DNA TREC and KREC — by-products of maturation of T- and B-cell receptors, which allows us to judge the defects of the T- and B-cell links of the immune system to predict infectious complications in children with CHD. The data of our own study of 200 infants with CHD (in 5% of cases with syndromic forms of CHD) are presented, where a decrease in TREC was found in 23.5% of cases, including all infants with syndromic forms, more often with cyanotic and conotruncal CHD and in children admitted in critical conditions. In children with reduced TREC values, infectious complications in the postoperative period were observed significantly more often than in children with normal indicators (36 and 3.6%, respectively). The analysis of publications confirmed the importance of TREC and KREC screening for targeted preoperative preparation in order to reduce postoperative complications and reduce the risk of mortality in CHD.

Predicting the impact of low-density lipoprotein cholesterol lowering through different drug targets on risk of congenital heart disease

Abstract Background Low-density lipoprotein cholesterol (LDL) lowering in pregnancy has been a controversial topic as observational studies have described an increased risk of congenital malformations. With the advent of new, long-lasting LDL lowering therapies such as silencing RNA therapies that exert clinical effects for up to six months after administration, there is substantial probability that women of childbearing age might conceive during the period of drug activity. Where clinical data is not available, the Mendelian randomization (MR) paradigm can be used to predict effects of drug target perturbation using genetic data. Purpose We aimed to leverage genetic data to explore the predicted impact of LDL lowering via the statin, ezetimibe and PCSK9 drug targets, on congenital heart disease. Methods Uncorrelated genome-wide significant (p&amp;lt;5x10-8) variants for LDL and their association estimates, overall and restricted to the HMGCR, NPC1L1, PCSK9 gene regions +/- 10kB, were extracted from GWAS summary data on the UK Biobank (n=469,897). Gene-outcome association data was extracted from GWAS results of FinnGen 8thRelease (n=342,499) for conotruncal defects, congenital malformations of the great arteries; septal defects; congenital disease of the aortic or mitral valves; and the vertebral, anorectal, cardiovascular, tracheo-esophageal, renal and limb anomaly (VACTERL) association. A drug-target MR analysis was carried out using inverse-variance weighted MR. Results Genetically-proxied LDL-lowering through PCSK9 associated with higher odds of VACTREL association (OR 1.70, 95%ci 1.25-2.32; p&amp;lt;0.001), conotruncal defects (OR 3.97, 95%CI 1.37-11.53, p=0.011) and overall congenital heart disease of any type (OR 1.49, 95%CII 1.08-2.05, p=0.015). Genetically-proxied LDL lowering via HMGCR was associated with higher odds of congenital malformations involving the great arteries (OR 5.85, 95%cCI 1.07-31.84, p=0.041). Genetically-proxied LDL lowering via NPC1L1 drug targets was not associated with differences in risk of congenital heart disease, though the power of these analyses was limited. Conclusions These data provide genetic evidence suggesting that use of LDL-lowering agents during pregnancy might influence risk of congenital heart disease. Importantly, due to underlying assumptions of the analysis, the results of this analysis are only applicable to drugs that are able to cross the placenta and exert direct effects on LDL metabolism in the fetus and they cannot be used to infer the indirect influence of lowering maternal LDL. The data support ongoing caution regarding statin use, and additionally suggest that long-lasting PCSK9-inhibiting agents that are able to cross the placenta, such as monoclonal antibodies and silencing RNA therapies, should be used with utmost caution in women planning to conceive.Figure 1