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Syncope can be a dramatic and frightening experience for the patient and onlookers. It can also be a confusing area for doctors, with a lack of diagnostic certainty and a differential that ranges from the completely benign to the life-threatening. This is a tricky area for clinicians, who can find it difficult to reassure their patients and their families. The aim of this article is to present a clear scheme for appropriate investigation and referral of paediatric patients with syncope. The aim of investigations in such cases should be to confirm or exclude serious, life-threatening causes of syncope. [ABSTRACT FROM AUTHOR]

Congenital heart disease (CHD) is the most common congenital anomaly, with an overall incidence of approximately 1% in the United Kingdom. Exome sequencing in large CHD cohorts has been performed to provide insights into the genetic aetiology of CHD. This includes a study of 1891 probands by our group in collaboration with others, which identified three novel genes—CDK13, PRKD1, and CHD4, in patients with syndromic CHD. PRKD1 encodes a serine/threonine protein kinase, which is important in a variety of fundamental cellular functions. Individuals with a heterozygous mutation in PRKD1 may have facial dysmorphism, ectodermal dysplasia and may have CHDs such as pulmonary stenosis, atrioventricular septal defects, coarctation of the aorta and bicuspid aortic valve. To obtain a greater appreciation for the role that this essential protein kinase plays in cardiogenesis and CHD, we have analysed a Prkd1 transgenic mouse model (Prkd1em1) carrying deletion of exon 2, causing loss of function. High‐resolution episcopic microscopy affords detailed morphological 3D analysis of the developing heart and provides evidence for an essential role of Prkd1 in both normal cardiac development and CHD. We show that homozygous deletion of Prkd1 is associated with complex forms of CHD such as atrioventricular septal defects, and bicuspid aortic and pulmonary valves, and is lethal. Even in heterozygotes, cardiac differences occur. However, given that 97% of Prkd1 heterozygous mice display normal heart development, it is likely that one normal allele is sufficient, with the defects seen most likely to represent sporadic events. Moreover, mRNA and protein expression levels were investigated by RT‐qPCR and western immunoblotting, respectively. A significant reduction in Prkd1 mRNA levels was seen in homozygotes, but not heterozygotes, compared to WT littermates. While a trend towards lower PRKD1 protein expression was seen in the heterozygotes, the difference was only significant in the homozygotes. There was no compensation by the related Prkd2 and Prkd3 at transcript level, as evidenced by RT‐qPCR. Overall, we demonstrate a vital role of Prkd1 in heart development and the aetiology of CHD. [ABSTRACT FROM AUTHOR]

Aortic root abscess without any involvement of the aortic valve is extremely rare. This report describes an 11-year-old girl with subperiosteal abscess due to a virulent organism called Panton-Valentine leukocidin-secreting staphylococci. Although her initial transthoracic echocardiogram did not show any cardiac abnormality, she subsequently experienced an aortic root abscess communicating with the left ventricle. The aortic valve was unaffected, and no other cardiac abnormality was detected at any stage. The girl made a complete recovery after surgical intervention for her aortic root abscess, which was increasing in size despite antibiotic therapy. Patients with such illnesses require close monitoring with repeated expert echocardiography and timely intervention. [ABSTRACT FROM AUTHOR]

Children with heart disease frequently require anticoagulation for thromboprophylaxis. Current standard of care (SOC), vitamin K antagonists or low-molecular-weight heparin, has significant disadvantages. The authors sought to describe safety, pharmacokinetics (PK), pharmacodynamics, and efficacy of apixaban, an oral, direct factor Xa inhibitor, for prevention of thromboembolism in children with congenital or acquired heart disease. Phase 2, open-label trial in children (ages, 28 days to <18 years) with heart disease requiring thromboprophylaxis. Randomization 2:1 apixaban or SOC for 1 year with intention-to-treat analysis. Primary endpoint: a composite of adjudicated major or clinically relevant nonmajor bleeding. Secondary endpoints: PK, pharmacodynamics, quality of life, and exploration of efficacy. From 2017 to 2021, 192 participants were randomized, 129 apixaban and 63 SOC. Diagnoses included single ventricle (74%), Kawasaki disease (14%), and other heart disease (12%). One apixaban participant (0.8%) and 3 with SOC (4.8%) had major or clinically relevant nonmajor bleeding (% difference −4.0 [95% CI: −12.8 to 0.8]). Apixaban incidence rate for all bleeding events was nearly twice the rate of SOC (100.0 vs 58.2 per 100 person-years), driven by 12 participants with ≥4 minor bleeding events. No thromboembolic events or deaths occurred in either arm. Apixaban pediatric PK steady-state exposures were consistent with adult levels. In this pediatric multinational, randomized trial, bleeding and thromboembolism were infrequent on apixaban and SOC. Apixaban PK data correlated well with adult trials that demonstrated efficacy. These results support the use of apixaban as an alternative to SOC for thromboprophylaxis in pediatric heart disease. (A Study of the Safety and Pharmacokinetics of Apixaban Versus Vitamin K Antagonist [VKA] or Low Molecular Weight Heparin [LMWH] in Pediatric Subjects With Congenital or Acquired Heart Disease Requiring Anticoagulation; NCT02981472) [Display omitted] [ABSTRACT FROM AUTHOR]

The article comments on the article of Doctor Browning Carmo about the use of intravenous prostagladin therapy (IPT) without routine mechanical ventilation in the transfer of an infant with heart disease to another hospital. IPT is well established for maintaining the arterial duct in newborn babies with duct dependent congenital heart disease. Elective intubation and ventilation is required for infants who are transferred between hospitals.

Background and objective: Different liquid formulations of a drug prepared for use in children cannot be assumed to have therapeutic equivalence. The objective of this study was to ascertain the interhospital constancy of unlicensed liquid captopril formulations used to treat children with heart failure in the UK. Design: A questionnaire-based telephone survey. Setting: 13 tertiary paediatric cardiac centres in the UK and 13 large hospitals referring patients to these centres. Participants: The study included pharmacists responsible for providing the pharmaceutical input to children with congenital heart disease or a pharmacist designated to cover paediatric services. Technical staff employed by "specials" manufacturers also participated. Results: Four hospitals dispensed captopril tablets for crushing and dissolving in water before administration; the remaining 22 used nine different liquid formulations of captopril. Only three cardiac centres and their referring hospitals were found to be using the same liquid captopril formulations; 10 centres and their referring hospitals were using completely different captopril formulations. Conclusions: This survey shows that paediatric cardiac centres and their referring hospitals use a variety of unlicensed liquid captopril formulations interchangeably. This degree of inconsistency raises issues about optimal captopril dosing and potential toxicity, such that its use may influence paediatric cardiac surgical and interventional outcomes. [ABSTRACT FROM AUTHOR]

Tropomyosin 1 (TPM1) is an essential sarcomeric component, stabilising the thin filament and facilitating actin's interaction with myosin. A number of sarcomeric proteins, such as alpha myosin heavy chain, play crucial roles in cardiac development. Mutations in these genes have been linked to congenital heart defects (CHDs), occurring in approximately 1 in 145 live births. To date, TPM1 has not been associated with isolated CHDs. Analysis of 380 CHD cases revealed three novel mutations in the TPM1 gene; IVS1 + 2T > C, I130V, S229F and a polyadenylation signal site variant GATAAA/AATAAA. Analysis of IVS1 + 2T > C revealed aberrant pre-mRNA splicing. In addition, abnormal structural properties were found in hearts transfected with TPM1 carrying I130V and S229F mutations. Phenotypic analysis of TPM1 morpholino-treated embryos revealed roles for TPM1 in cardiac looping, atrial septation and ventricular trabeculae formation and increased apoptosis was seen within the heart. In addition, sarcomere assembly was affected and altered action potentials were exhibited. This study demonstrated that sarcomeric TPM1 plays vital roles in cardiogenesis and is a suitable candidate gene for screening individuals with isolated CHDs. [ABSTRACT FROM AUTHOR]

The commonest autosomal deletion, 22q11.2 deletion syndrome (22q11DS) is a multisystem disorder varying greatly in severity and age of identification between affected individuals. Holistic care is best served by a multidisciplinary team, with an anticipatory approach. Priorities tend to change with age, from feeding difficulties, infections and surgery of congenital abnormalities particularly of the heart and velopharynx in infancy and early childhood to longer-term communication, learning, behavioural and mental health difficulties best served by evaluation at intervals to consider and initiate management. Regular monitoring of growth, endocrine status, haematological and immune function to enable early intervention helps in maintaining health. Conclusion: Guidelines to best practice management of 22q11DS based on a literature review and consensus have been developed by a national group of professionals with consideration of the limitations of available medical and educational resources. [ABSTRACT FROM AUTHOR]

Background: Epidemiological studies indicate a substantial excess familial recurrence of non-syndromic Tetralogy of Fallot (TOF), implicating genetic factors that remain largely unknown. The Rho induced kinase 1 gene (ROCK1) is a key component of the planar cell polarity signalling pathway, which plays an important role in normal cardiac development. The aim of this study was to investigate the role of genetic variation in ROCK1 on the risk of TOF. Results: ROCK1 was sequenced in a discovery cohort of 93 non-syndromic TOF probands to identify rare variants. TagSNPs were selected to capture commoner variation in ROCK1. Novel variants and TagSNPs were genotyped in a discovery cohort of 458 TOF cases and 1331 healthy controls, and positive findings were replicated in a further 209 TOF cases and 1290 healthy controls. Association between genotypes and TOF was assessed using LAMP. A rare SNP (c.807C > T; rs56085230) discovered by sequencing was associated with TOF risk (p = 0.006) in the discovery cohort. The variant was also significantly associated with the risk of TOF in the replication cohort (p = 0.018). In the combined cohorts the odds ratio for TOF was 2.61 (95% CI 1.58-4.30); p < 0.0001. The minor allele frequency of rs56085230 in the cases was 0.02, and in the controls it was 0.007. The variant accounted for 1% of the population attributable risk (PAR) of TOF. We also found significant association with TOF for an uncommon TagSNP in ROCK1, rs288979 (OR 1.64 [95% CI 1.15-2.30]; p = 1.5x10-5). The minor allele frequency of rs288979 in the controls was 0.043, and the variant accounted for 11% of the PAR of TOF. These association signals were independent of each other, providing additional internal validation of our result. Conclusions: Low frequency intermediate penetrance (LFIP) variants in the ROCK1 gene predispose to the risk of TOF. [ABSTRACT FROM AUTHOR]

Several previous studies have investigated the role of common promoter variants in the vascular endothelial growth factor (VEGF) gene in causing congenital cardiovascular malformation (CVM). However, results have been discrepant between studies and no study to date has comprehensively characterised variation throughout the gene. We genotyped 771 CVM cases, of whom 595 had the outflow tract malformation Tetralogy of Fallot (TOF), and carried out TDT and case-control analyses using haplotype-tagging SNPs in VEGF. We carried out a meta-analysis of previous case-control or family-based studies that had typed VEGF promoter SNPs, which included an additional 570 CVM cases. To identify rare variants potentially causative of CVM, we carried out mutation screening in all VEGF exons and splice sites in 93 TOF cases. There was no significant effect of any VEGF haplotype-tagging SNP on the risk of CVM in our analyses of 771 probands. When the results of this and all previous studies were combined, there was no significant effect of the VEGF promoter SNPs rs699947 (OR 1.05 [95% CI 0.95-1.17]); rs1570360 (OR 1.17 [95% CI 0.99-1.26]); and rs2010963 (OR 1.04 [95% CI 0.93-1.16]) on the risk of CVM in 1341 cases. Mutation screening of 93 TOF cases revealed no VEGF coding sequence variants and no changes at splice consensus sequences. Genetic variation in VEGF appears to play a small role, if any, in outflow tract CVM susceptibility. [ABSTRACT FROM AUTHOR]

Abstract: Objective: To assess the performance of the bovine Contegra® valved conduit used for right ventricular (RV) outflow tract reconstruction, particularly in relation to post-operative RV pressure. Methods: Follow-up study of 64 consecutive right ventricular to pulmonary artery-conduit implants in 62 patients between January 2000 and April 2003. The majority of cases were forms of pulmonary atresia/VSD (n =24, 39%) or Fallot's tetralogy (n =13, 21%). Thirteen cases (21%) had aortic atresia, truncus arteriosus or discordant connections with pulmonary atresia/VSD. Twelve cases (19%) were conduit replacements. Echocardiography was performed for a median follow-up of 14 months (range 0–38 months). Results: Median age at implantation was 13.8 months (range 0.1–244 months) and median weight was 8.9kg (range 2.1–84.1kg). Thirty-eight patients (59.4%) were <10kg at the time of surgery. Early mortality was 6.4% (n =4). During follow-up there were four explantations (one for endocarditis and three for conduit dilatation) and 16 (28.6%) catheter interventions. Overall freedom from intervention at 1 and 3 years was 71±6% and 53±11%, respectively. Freedom from conduit-specific reintervention was 66±11% at the end of the study period. Reintervention was associated with small conduits (p =0.04), age <1 year (p =0.04) and with high RV/LV pressure ratio in the immediate post-operative period (p =0.0003). On multivariate analysis, the RV/LV pressure ratio was the strongest single factor predicting the overall reintervention (OR 5.45). Acquired distal conduit stenosis at suture line was the commonest indication for conduit-specific reintervention and was associated with the smaller conduits. The conduits explanted for dilatation showed neointimal proliferation, thrombosis, calcification and chronic inflammation. Conclusions: The Contegra conduit is widely applicable to RVOT reconstruction with satisfactory mid-term results. However, there is a significant incidence of conduit-related complications, particularly with the smaller conduits. Adverse performance was strongly associated with high RV/LV pressure ratio at completion of surgery. We would recommend cautious use of the conduits in patients with predicted high RV/LV pressure ratios, where careful monitoring of conduit performance is crucial. There is some element of unpredictability, which adds to the importance of close follow-up. Further studies are needed to explore the issues of thrombogenicity, degeneration, possible ‘rejection’, and the potential role of anti-platelet and anti-inflammatory modulation. [Copyright &y& Elsevier]