Recent Submissions

  • Apixaban for prevention of thromboembolism in pediatric heart disease

    Bu'Lock, Frances (2023-12-12)
    Background: 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. Objectives: 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. Methods: 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. Results: 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. Conclusions: 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).
  • PAEDIATRIC VASCULAR SURGERY: A review of cases from a dedicated paediatric vascular surgery clinic

    Kay, Mark (2023-11-06)
    Background: The experience in paediatric vascular diseases is limited in the UK and worldwide due to their rarity and variations in practice. We looked at types of cases presenting to a dedicated paediatric vascular clinic. Methods: Medical records of children seen in a dedicated paediatric vascular clinic at a tertiary referral service between 2016 and 2022 were reviewed. These patients were either seen for the first time in that clinic or had their appointments as a follow up after inpatient review or intervention while being under care of paediatric teams in local hospitals. Results: 55 patients (34 males) were seen aged between 4 months and 17 years (mean 9.5 years). Common presentations were limb length discrepancy secondary to iatrogenic arterial occlusion, follow up after bypass for trauma, lower limb swelling or discolouration and varicose veins. Operative procedures included lower limb bypass, angioplasty, ligation of aneurysms and varicose vein surgery. Conclusion: Paediatric vascular conditions are uncommon and therefore most vascular surgeons and trainees will have little exposure to such cases. Intervention is needed for arterial injury secondary to penetrating or iatrogenic trauma. National registry is required for these rare cases to gain prospective data that can help build up more evidence for educational purposes and to establish guidelines.
  • Sudden cardiac death in childhood RASopathy-associated hypertrophic cardiomyopathy: Validation of the HCM risk-kids model and predictors of events

    Linter, Katie (28/09/2023)
    Background: RASopathies account for nearly 20% of cases of childhood hypertrophic cardiomyopathy (HCM). Sudden cardiac death (SCD) occurs in patients with RASopathy-associated HCM, but the risk factors for SCD have not been systematically evaluated. Aim: To validate the HCM Risk-Kids SCD risk prediction model in children with RASopathy-associated HCM and investigate potential specific SCD predictors in this population. Methods: Validation of HCM Risk-Kids was performed in a retrospective cohort of 169 patients with a RASopathy-associated HCM from 15 international paediatric cardiology centres. Multiple imputation by chained equations was used for missing values related to the HCM Risk-Kids parameters. Results: Eleven patients (6.5%) experienced a SCD or equivalent event at a median age of 12.5 months (IQR 7.7-28.64). The calculated SCD/equivalent event incidence was 0.78 (95% CI 0.43-1.41) per 100 patient years. Six patients (54.54%) with an event were in the low-risk category according to the HCM Risk-Kids model. Harrell's C index was 0.60, with a sensitivity of 9.09%, specificity of 63.92%, positive predictive value of 1.72%, and negative predictive value of 91%; with a poor distinction between the different risk groups. Unexplained syncope (HR 42.17, 95% CI 10.49-169.56, p < 0.001) and non-sustained ventricular tachycardia (HR 5.48, 95% CI 1.58-19.03, p < 0.007) were predictors of SCD on univariate analysis. Conclusion: Unexplained syncope and the presence of NSVT emerge as predictors for SCD in children with RASopathy-associated HCM. The HCM Risk-Kids model may not be appropriate to use in this population, but larger multicentre collaborative studies are required to investigate this further.
  • Outcome monitoring and risk stratification after cardiac procedure in neonates, infants, children and young adults born with congenital heart disease: protocol for a multicentre prospective cohort study (Children OMACp)

    Omeje, Ikenna (2023-08-08)
    Introduction: Congenital heart disease (CHD) represents the most common birth defect, affecting from 0.4% to 1.2% of children born in developed countries. The survival of these patients has increased significantly, but CHD remains one of the major causes of neonatal and childhood death. The aetiology of CHD is complex, with some evidence of both genetic and environmental causes. However, there is still lack of knowledge regarding modifiable risk factors and molecular and genetic mechanisms underlying the development of CHD. This study aims to develop a prospective cohort of patients undergoing cardiac procedures that will bring together routinely collected clinical data and biological samples from patients and their biological mothers, in order to investigate risk factors and predictors of postoperative-outcomes, as well as better understanding the effect of the surgical intervention on the early and long-term outcomes. Methods and analysis: Children OMACp (OMACp, outcome monitoring after cardiac procedure in congenital heart disease) is a multicentre, prospective cohort study recruiting children with CHD undergoing a cardiac procedure. The study aims to recruit 3000 participants over 5 years (2019-2024) across multiple UK sites. Routine clinical data will be collected, as well as participant questionnaires collecting sociodemographic, NHS resource use and quality of life data. Biological samples (blood, urine and surgical waste tissue from patients, and blood and urine samples from biological mothers) will be collected where consent has been obtained. Follow-up outcome and questionnaire data will be collected for 5 years. Ethics and dissemination: The study was approved by the London-Brent Research Ethics Committee on 30 July 2019 (19/SW/0113). Participants (or their parent/guardian if under 16 years of age) must provide informed consent prior to being recruited into the study. Mothers who wish to take part must also provide informed consent prior to being recruited. The study is sponsored by University Hospitals Bristol and Weston Foundation Trust and is managed by the University of Bristol. Children OMACp is adopted onto the National Institute for Health Research Clinical Research Network portfolio. Findings will be disseminated through peer-reviewed publications, presentation at conference, meetings and through patient organisations and newsletters. Trial registration number: ISRCTN17650644.
  • Cardiac muscle training-A new way of recognizing and supporting recovery for LVAD patients in the pediatric population

    Kantzis, Marinos (2022-10-22)
    Patients with refractory heart failure due to chronic progressive cardiac myopathy (CM) may require mechanical circulatory support as a bridge to transplantation. A few patients can be weaned from support devices if recovery can be achieved. The identification of these patients is of great importance as recovery may be missed if the heart is unloaded by the ventricular assist device (VAD). Testing the load-bearing capacity of the supported left ventricle (LV) by temporarily and gradually reducing mechanical support during cardiac exercise can help identify responders and potentially aid the recovery process. An exercise training protocol was used in 3 patients (8 months, 18 months and 8 years old) with histological CM findings and myocarditis. They were monitored regularly using clinical information and functional imaging with VAD support. Echocardiographic examination included both conventional real-time 3D echocardiography (RT3DE) and speckle tracking (ST). A daily temporary reduction in pump rate (phase A) was followed by a permanent reduction in rate (phase B). Finally, pump stops of up to 30 min were performed once a week (phase C). The final decision on explantation was based on at least three pump stops. Two patients were weaned and successfully removed from the VAD. One of them was diagnosed with acute viral myocarditis. The other had chronic myocarditis with dilated myopathy and mild interstitial fibrosis. The noninvasive assessment of cardiac output and strain under different loading conditions during VAD therapy is feasible and helps identify candidates for weaning despite severe histological findings. The presented protocol, which incorporates new echocardiographic techniques for determining volume and deformation, can be of great help in positively guiding the process of individual recovery, which may be essential for selecting and increasing the number of patients to be weaned from VAD.
  • Paediatric brain MRI findings following congenital heart surgery: a systematic review

    Bu'Lock, Frances (2022-03-22)
    Objective: This systematic review aimed to establish the relative incidence of new postoperative brain MRI findings following paediatric congenital cardiac surgery. Design: To distinguish perioperative changes from pre-existing MR findings, our systematic search strategy focused on identifying original research studies reporting both presurgery and postsurgery brain MRI scans. Patient demographics, study methods and brain MR findings were extracted. Results: Twenty-one eligible publications, including two case-control and one randomised controlled trial, were identified. Pre-existing brain MRI findings were noted in 43% (513/1205) of neonates prior to surgery, mainly white matter injuries (WMI). Surgery was performed at a median age of 8 days with comparison of preoperative and postoperative MR scans revealing additional new postoperative findings in 51% (550/1075) of patients, mainly WMI. Four studies adopted a brain injury scoring system, but the majority did not indicate the severity or time course of findings. In a subgroup analysis, approximately 32% of patients with pre-existing lesions went on to develop additional new lesions postsurgery. Pre-existing findings were not found to confer a higher risk of acquiring brain lesions postoperatively. No evidence was identified linking new MR findings with later neurodevelopmental delay. Conclusion: This systematic review suggests that surgery approximately doubles the number of patients with new brain lesions.
  • Elucidation of the genetic causes of bicuspid aortic valve disease

    Nelson, Christopher; Bolger, Aidan; Samani, Nilesh (2022-06-21)
    Aims: The present study aims to characterise the genetic risk architecture of bicuspid aortic valve (BAV) disease, the most common congenital heart defect. Methods and results: We carried out a genome-wide association study (GWAS) including 2,236 BAV patients and 11,604 controls. This led to the identification of a new risk locus for BAV on chromosome 3q29. The single nucleotide polymorphism (SNP) rs2550262 was genome-wide significant BAV-associated (P = 3.49 × 10-08) and was replicated in an independent case-control sample. The risk locus encodes a deleterious missense variant in MUC4 (p.Ala4821Ser), a gene that is involved in epithelial-to-mesenchymal transformation. Mechanistical studies in zebrafish revealed that loss of Muc4 led to a delay in cardiac valvular development suggesting that loss of MUC4 may also play a role in aortic valve malformation. The GWAS also confirmed previously reported BAV risk loci at PALMD (P = 3.97 × 10-16), GATA4 (P = 1.61 × 10-09), and TEX41 (P = 7.68 × 10-04). In addition, the genetic BAV architecture was examined beyond the single-marker level revealing that a substantial fraction of BAV heritability is polygenic and approximately 20% of the observed heritability can be explained by our GWAS data. Furthermore, we used the largest human single cell atlas for foetal gene expression and show that the transcriptome profile in endothelial cells is a major source contributing to BAV pathology. Conclusion: Our study provides a deeper understanding of the genetic risk architecture of BAV formation on the single-marker and polygenic level.
  • Ebstein's anomaly: From fetus to adult-literature review and pathway for patient care

    Shebani, Suhair (2022-04-23)
    Ebstein's anomaly, first described in 1866 by Dr William Ebstein, accounts for 0.3-0.5% of congenital heart defects and represents 40% of congenital tricuspid valve abnormalities. Ebstein's anomaly affects the development of the tricuspid valve with widely varying morphology and, therefore, clinical presentation. Associated congenital cardiac lesions tend to be found more often in younger patients and may even be the reason for presentation. Presentation can vary from the most extreme form in fetal life, to asymptomatic diagnosis late in adult life. The most symptomatic patients need intensive care support in the neonatal period. This article summarizes and analyzes the literature on Ebstein's anomaly and provides a framework for the investigation, management, and follow-up of these patients, whether they present via fetal detection or late in adult life. For each age group, the clinical presentation, required diagnostic investigations, natural history, and management are described. The surgical options available for patients with Ebstein's anomaly are detailed and analyzed, starting from the initial mono-leaflet repairs to the most recent cone repair and its modifications. The review also assesses the effects of pregnancy on the Ebstein's circulation, and vice versa, the effects of Ebstein's on pregnancy outcomes. Finally, two attached appendices are provided for a structured echocardiogram protocol and key information useful for comprehensive Multi-Disciplinary Team discussion.
  • Friedreich's ataxia-associated childhood hypertrophic cardiomyopathy: a national cohort study

    Linter, Katie (2021-10-05)
    Objective: Hypertrophic cardiomyopathy (HCM) is an important predictor of long-term outcomes in Friedreich's ataxia (FA), but the clinical spectrum and survival in childhood is poorly described. This study aimed to describe the clinical characteristics of children with FA-HCM. Design and setting: Retrospective, longitudinal cohort study of children with FA-HCM from the UK. Patients: 78 children (<18 years) with FA-HCM diagnosed over four decades. Intervention: Anonymised retrospective demographic and clinical data were collected from baseline evaluation and follow-up. Main outcome measures: The primary study end-point was all-cause mortality (sudden cardiac death, atrial arrhythmia-related death, heart failure-related death, non-cardiac death) or cardiac transplantation. Results: The mean age at diagnosis of FA-HCM was 10.9 (±3.1) years. Diagnosis was within 1 year of cardiac referral in 34 (65.0%) patients, but preceded the diagnosis of FA in 4 (5.3%). At baseline, 65 (90.3%) had concentric left ventricular hypertrophy and 6 (12.5%) had systolic impairment. Over a median follow-up of 5.1 years (IQR 2.4-7.3), 8 (10.5%) had documented supraventricular arrhythmias and 8 (10.5%) died (atrial arrhythmia-related n=2; heart failure-related n=1; non-cardiac n=2; or unknown cause n=3), but there were no sudden cardiac deaths. Freedom from death or transplantation at 10 years was 80.8% (95% CI 62.5 to 90.8). Conclusions: This is the largest cohort of childhood FA-HCM reported to date and describes a high prevalence of atrial arrhythmias and impaired systolic function in childhood, suggesting early progression to end-stage disease. Overall mortality is similar to that reported in non-syndromic childhood HCM, but no patients died suddenly.
  • Pregnancies in women with Turner syndrome: a retrospective multicentre UK study

    Bolger, Aidan; Siddiqui, Farah (2021-11-20)
    Objective: To determine the characteristics and outcomes of pregnancy in women with Turner syndrome. Design: Retrospective 20-year cohort study (2000-20). Setting: Sixteen tertiary referral maternity units in the UK. Population or sample: A total of 81 women with Turner syndrome who became pregnant. Methods: Retrospective chart analysis. Main outcome measures: Mode of conception, pregnancy outcomes. Results: We obtained data on 127 pregnancies in 81 women with a Turner phenotype. All non-spontaneous pregnancies (54/127; 42.5%) were by egg donation. Only 9/31 (29%) pregnancies in women with karyotype 45,X were spontaneous, compared with 53/66 (80.3%) pregnancies in women with mosaic karyotype 45,X/46,XX (P < 0.0001). Women with mosaic karyotype 45,X/46,XX were younger at first pregnancy by 5.5-8.5 years compared with other Turner syndrome karyotype groups (P < 0.001), and more likely to have a spontaneous menarche (75.8% versus 50% or less, P = 0.008). There were 17 miscarriages, three terminations of pregnancy, two stillbirths and 105 live births. Two women had aortic dissection (2.5%); both were 45,X karyotype with bicuspid aortic valves and ovum donation pregnancies, one died. Another woman had an aortic root replacement within 6 months of delivery. Ten of 106 (9.4%) births with gestational age data were preterm and 22/96 (22.9%) singleton infants with birthweight/gestational age data weighed less than the tenth centile. The caesarean section rate was 72/107 (67.3%). In only 73/127 (57.4%) pregnancies was there documentation of cardiovascular imaging within the 24 months before conceiving. Conclusions: Pregnancy in women with Turner syndrome is associated with major maternal cardiovascular risks; these women deserve thorough cardiovascular assessment and counselling before assisted or spontaneous pregnancy managed by a specialist team. Tweetable abstract: Pregnancy in women with Turner syndrome is associated with an increased risk of aortic dissection.
  • Relationship between maximal left ventricular wall thickness and sudden cardiac death in childhood onset hypertrophic cardiomyopathy

    Linter, Katie (2022-05-02)
    Background: Maximal left ventricular wall thickness (MLVWT) is a risk factor for sudden cardiac death (SCD) in hypertrophic cardiomyopathy (HCM). In adults, the severity of left ventricular hypertrophy has a nonlinear relationship with SCD, but it is not known whether the same complex relationship is seen in childhood. The aim of this study was to describe the relationship between left ventricular hypertrophy and SCD risk in a large international pediatric HCM cohort. Methods: The study cohort comprised 1075 children (mean age, 10.2 years [±4.4]) diagnosed with HCM (1-16 years) from the International Paediatric Hypertrophic Cardiomyopathy Consortium. Anonymized, noninvasive clinical data were collected from baseline evaluation and follow-up, and 5-year estimated SCD risk was calculated (HCM Risk-Kids). Results: MLVWT Z score was <10 in 598 (58.1%), ≥10 to <20 in 334 (31.1%), and ≥20 in 143 (13.3%). Higher MLVWT Z scores were associated with heart failure symptoms, unexplained syncope, left ventricular outflow tract obstruction, left atrial dilatation, and nonsustained ventricular tachycardia. One hundred twenty-two patients (71.3%) with MLVWT Z score ≥20 had coexisting risk factors for SCD. Over a median follow-up of 4.9 years (interquartile range, 2.3-9.3), 115 (10.7%) had an SCD event. Freedom from SCD event at 5 years for those with MLVWT Z scores <10, ≥10 to <20, and ≥20 was 95.6%, 87.4%, and 86.0, respectively. The estimated SCD risk at 5 years had a nonlinear, inverted U-shaped relationship with MLVWT Z score, peaking at Z score +23. The presence of coexisting risk factors had a summative effect on risk. Conclusions: In children with HCM, an inverted U-shaped relationship exists between left ventricular hypertrophy and estimated SCD risk. The presence of additional risk factors has a summative effect on risk. While MLVWT is important for risk stratification, it should not be used either as a binary variable or in isolation to guide implantable cardioverter defibrillator implantation decisions in children with HCM.
  • Clinical features and natural history of preadolescent nonsyndromic hypertrophic cardiomyopathy

    Linter, Katie (2022-05-24)
    Background: Up to one-half of childhood sarcomeric hypertrophic cardiomyopathy (HCM) presents before the age of 12 years, but this patient group has not been systematically characterized. Objectives: The aim of this study was to describe the clinical presentation and natural history of patients presenting with nonsyndromic HCM before the age of 12 years. Methods: Data from the International Paediatric Hypertrophic Cardiomyopathy Consortium on 639 children diagnosed with HCM younger than 12 years were collected and compared with those from 568 children diagnosed between 12 and 16 years. Results: At baseline, 339 patients (53.6%) had family histories of HCM, 132 (20.9%) had heart failure symptoms, and 250 (39.2%) were prescribed cardiac medications. The median maximal left ventricular wall thickness z-score was 8.7 (IQR: 5.3-14.4), and 145 patients (27.2%) had left ventricular outflow tract obstruction. Over a median follow-up period of 5.6 years (IQR: 2.3-10.0 years), 42 patients (6.6%) died, 21 (3.3%) underwent cardiac transplantation, and 69 (10.8%) had life-threatening arrhythmic events. Compared with those presenting after 12 years, a higher proportion of younger patients underwent myectomy (10.5% vs 7.2%; P = 0.045), but fewer received primary prevention implantable cardioverter-defibrillators (18.9% vs 30.1%; P = 0.041). The incidence of mortality or life-threatening arrhythmic events did not differ, but events occurred at a younger age. Conclusions: Early-onset childhood HCM is associated with a comparable symptom burden and cardiac phenotype as in patients presenting later in childhood. Long-term outcomes including mortality did not differ by age of presentation, but patients presenting at younger than 12 years experienced adverse events at younger ages.
  • Mechanistic insights on the effect of crocin, an active ingredient of saffron, on atherosclerosis in apolipoprotein E knockout mice

    Kotidis, Charalampos (2022-08)
    Background: We investigated the effect of crocin treatment on atherosclerosis and serum lipids in apolipoprotein E knockout (ApoE-/-) mice, focusing on the expression of endothelial nitric oxide synthase (eNOS) and hypoxia-induced factor-1 alpha (HIF-1α). Methods: Sixty-two animals were divided into two groups and randomly allocated to crocin (100 mg/kg/day) in drinking water or no crocin. All mice were maintained on standard chow diet containing 5% fat. Crocin was initiated at the 16th week of age and continued for 16 additional weeks. At 32 weeks of age, after blood sampling for plasma lipid determination and euthanasia, proximal aorta was removed and 3 μm sections were used to measure the atherosclerotic area and determine the expression of eNOS and HIF-1α by immunohistochemistry. Results: Each group consisted of 31 animals (17 males and 14 females in each group). Crocin significantly reduced the atherosclerotic area (mm2 ± SEM) in treated mice compared to controls, both in males (0.0798 ± 0.017 vs. 0.1918 ± 0.028, P < 0.002, respectively) and females (0.0986 ± 0.023 vs. 0.1765 ± 0.025, P < 0.03, respectively). eNOS expression was significantly increased in crocin-treated mice compared to controls, both in males (2.77 ± 0.24 vs. 1.50 ± 0.34, P=0.004, respectively) and females (3.41 ± 0.37 vs. 1.16 ± 0.44, P=0.003, respectively). HIF-1α expression was significantly decreased in crocin-treated mice compared to controls, both in males (21.25 ± 2.14 vs. 156.5 ± 6.67, P < 0.001, respectively) and females (35.3 ± 7.20 vs. 113.3 ± 9.0, P < 0.01, respectively). No difference was noticed in total, low- and high-density lipoprotein cholesterol between treated and control mice. Conclusion: Crocin reduces atherosclerosis possibly by modulation of eNOS and HIF-1α expression in ApoE-/- mice without affecting plasma cholesterol.
  • Clinical presentation and long-term outcomes of infantile hypertrophic cardiomyopathy: a European multicentre study

    Linter, Katie (2021-05-12)
    Aims: Children presenting with hypertrophic cardiomyopathy (HCM) in infancy are reported to have a poor prognosis, but this heterogeneous group has not been systematically characterized. This study aimed to describe the aetiology, phenotype, and outcomes of infantile HCM in a well-characterized multicentre European cohort. Methods and results: Of 301 children diagnosed with infantile HCM between 1987 and 2019 presenting to 17 European centres [male n = 187 (62.1%)], underlying aetiology was non-syndromic (n = 138, 45.6%), RASopathy (n = 101, 33.6%), or inborn error of metabolism (IEM) (n = 49, 16.3%). The most common reasons for presentation were symptoms (n = 77, 29.3%), which were more prevalent in those with syndromic disease (n = 62, 61.4%, P < 0.001), and an isolated murmur (n = 75, 28.5%). One hundred and sixty-one (53.5%) had one or more co-morbidities. Genetic testing was performed in 163 (54.2%) patients, with a disease-causing variant identified in 115 (70.6%). Over median follow-up of 4.1 years, 50 (16.6%) underwent one or more surgical interventions; 15 (5.0%) had an arrhythmic event (6 in the first year of life); and 48 (15.9%) died, with an overall 5 year survival of 85%. Predictors of all-cause mortality were an underlying diagnosis of IEM [hazard ratio (HR) 4.4, P = 0.070], cardiac symptoms (HR 3.2, P = 0.005), and impaired left ventricular systolic function (HR 3.0, P = 0.028). Conclusions: This large, multicentre study of infantile HCM describes a complex cohort of patients with a diverse phenotypic spectrum and clinical course. Although overall outcomes were poor, this was largely related to underlying aetiology emphasizing the importance of comprehensive aetiological investigations, including genetic testing, in infantile HCM.
  • Contribution of NOTCH1 genetic variants to bicuspid aortic valve and other congenital lesions

    Debiec, Radoslaw; Safwan, Kassem; Sosin, Michael; Hetherington, Simon; Elamin, Mohamed; Coolman, Sue; Skinner, Gregory; Samani, Nilesh; Bolger, Aidan (2022-03)
    Introduction: Bicuspid aortic valve (BAV) affects 1% of the general population. NOTCH1 was the first gene associated with BAV. The proportion of familial and sporadic BAV disease attributed to NOTCH1 mutations has not been estimated. Aim: The aim of our study was to provide an estimate of familial and sporadic BAV disease attributable to NOTCH1 mutations. Methods: The population of our study consisted of participants of the University of Leicester Bicuspid aoRtic vAlVe gEnetic research-8 pedigrees with multiple affected family members and 381 sporadic patients. All subjects underwent NOTCH1 sequencing. A systematic literature search was performed in the NCBI PubMed database to identify publications reporting NOTCH1 sequencing in context of congenital heart disease. Results: NOTCH1 sequencing in 36 subjects from 8 pedigrees identified one variant c.873C>G/p.Tyr291* meeting the American College of Medical Genetics and Genomics criteria for pathogenicity. No pathogenic or likely pathogenic NOTCH1 variants were identified in 381 sporadic patients. Literature review identified 64 relevant publication reporting NOTCH1 sequencing in 528 pedigrees and 9449 sporadic subjects. After excluding families with syndromic disease pathogenic and likely pathogenic NOTCH1 variants were detected in 9/435 (2.1%; 95% CI: 0.7% to 3.4%) of pedigrees and between 0.05% (95% CI: 0.005% to 0.10%) and 0.08% (95% CI: 0.02% to 0.13%) of sporadic patients. Incomplete penetrance of definitely pathogenic NOTCH1 mutations was observed in almost half of reported pedigrees. Conclusions: Pathogenic and likely pathogenic NOTCH1 genetic variants explain 2% of familial and <0.1% of sporadic BAV disease and are more likely to associate with tetralogy of Fallot and hypoplastic left heart.
  • Making sense of the paediatric ECG: rate and rhythm

    Oakley, Chris (2022)
    No abstract available.
  • Making sense of the paediatric ECG

    Oakley, Chris (2022)
    No abstract available.
  • Paediatric and adult congenital cardiology education and training in Europe

    Bu'Lock, Frances (2022)
    Background: Limited data exist on training of European paediatric and adult congenital cardiologists. Methods: A structured and approved questionnaire was circulated to national delegates of Association for European Paediatric and Congenital Cardiology in 33 European countries. Results: Delegates from 30 countries (91%) responded. Paediatric cardiology was not recognised as a distinct speciality by the respective ministry of Health in seven countries (23%). Twenty countries (67%) have formally accredited paediatric cardiology training programmes, seven (23%) have substantial informal (not accredited or certified) training, and three (10%) have very limited or no programme. Twenty-two countries have a curriculum. Twelve countries have a national training director. There was one paediatric cardiology centre per 2.66 million population (range 0.87-9.64 million), one cardiac surgical centre per 4.73 million population (range 1.63-10.72 million), and one training centre per 4.29 million population (range 1.63-10.72 million population). The median number of paediatric cardiology fellows per training programme was 4 (range 1-17), and duration of training was 3 years (range 2-5 years). An exit examination in paediatric cardiology was conducted in 16 countries (53%) and certification provided by 20 countries (67%). Paediatric cardiologist number is affected by gross domestic product (R2 = 0.41). Conclusion: Training varies markedly across European countries. Although formal fellowship programmes exist in many countries, several countries have informal training or no training. Only a minority of countries provide both exit examination and certification. Harmonisation of training and standardisation of exit examination and certification could reduce variation in training thereby promoting high-quality care by European congenital cardiologists.
  • Medical education and training within congenital cardiology: current global status and future directions in a post COVID-19 world

    Bu'Lock, Frances (2022)
    Despite enormous strides in our field with respect to patient care, there has been surprisingly limited dialogue on how to train and educate the next generation of congenital cardiologists. This paper reviews the current status of training and evolving developments in medical education pertinent to congenital cardiology. The adoption of competency-based medical education has been lauded as a robust framework for contemporary medical education over the last two decades. However, inconsistencies in frameworks across different jurisdictions remain, and bridging gaps between competency frameworks and clinical practice has proved challenging. Entrustable professional activities have been proposed as a solution, but integration of such activities into busy clinical cardiology practices will present its own challenges. Consequently, this pivot towards a more structured approach to medical education necessitates the widespread availability of appropriately trained medical educationalists, a development that will better inform curriculum development, instructional design, and assessment. Differentiation between superficial and deep learning, the vital role of rich formative feedback and coaching, should guide our trainees to become self-regulated learners, capable of critical reasoning yet retaining an awareness of uncertainty and ambiguity. Furthermore, disruptive innovations such as "technology enhanced learning" may be leveraged to improve education, especially for trainees from low- and middle-income countries. Each of these initiatives will require resources, widespread advocacy and raised awareness, and publication of supporting data, and so it is especially gratifying that Cardiology in the Young has fostered a progressive approach, agreeing to publish one or two articles in each journal issue in this domain.