Paediatric heart failure - understanding the pathophysiology and the current role of cardiac biomarkers in clinical practice.

INTRODUCTION: Paediatric heart failure is a common clinical syndrome that may be experienced by children with congenital heart disease (CHD) and/or cardiomyopathy. It is characterised by clinical signs/symptoms which reflect the underlying pathophysiology based on one of three main clinical states: Pulmonary over-circulation, pressure overload, and ventricular failure. Current diagnosis relies on clinical assessment and echocardiogram imaging as cardiac biomarkers has been predominantly scientific to date. This review provides a comprehensive overview of paediatric heart failure pathophysiology and considers the available evidence for cardiac biomarkers in this setting. METHODS: A literature review was completed using MEDLINE ALL, EMBASE, and PubMed on 10th November, 2022. Search terms included biomarkers, heart failure, heart defects, congenital heart disease, fontan circulation, single ventricle circulation, cardiomyopathy, and child. This allowed the identification of individual cardiac biomarkers which are the focus of this review. These included NT-proBNP, MR-proANP, MR-proADM, troponin, sST2, galectin 3, and growth differentiation factor-15. RESULTS: Paediatric studies have established reference ranges for NT-proBNP and troponin for children with structurally normal hearts. Of all the biomarkers reviewed, NT-proBNP appears to correlate most closely with symptoms of heart failure and ventricular dysfunction on echocardiogram. However, there remains limited longitudinal data for NT-proBNP, and no validated reference ranges for patients with CHD and/or cardiomyopathy. None of the other biomarkers reviewed were consistently superior to NT-proBNP. CONCLUSION: Further large paediatric studies of patients with heart failure are needed to validate NT-proBNP in CHD and to evaluate the role of novel biomarkers in specific types of CHD, e.g. single ventricle physiology.

How to interpret cardiac biomarkers in children?

Cardiac biomarkers are used as first-line diagnostic tools in suspected myocardial injury and heart failure in adult patients. Their use in paediatric patients has been limited by variability caused by age, gender and the presence of an underlying congenital cardiac condition. There are established reference ranges for both NT-proBNP and troponin in healthy children, but these cannot be applied to all paediatric patients because of limited large studies focusing on children with congenital heart disease and/or cardiomyopathy.This article will focus on the pathophysiology of myocardial injury and heart failure in children and the subsequent cardiac biomarker correlation. It will explain how to interpret the biomarker assay levels obtained for both troponin and NT-proBNP and highlights the importance of a clear clinical question prior to requesting a cardiac biomarker assay level.Clinical cases outline scenarios that may prompt consideration of biomarker analysis in children and aims to equip the reader with an understanding of how to interpret the results.

Prevalence and trends of congenital heart defects among live births from 2005 to 2014 in Northern Ireland.

RATIONALE: Congenital heart defects (CHD) are the most frequent group of congenital anomalies representing a significant burden of mortality and morbidity and health service load. OBJECTIVE: In the Northern Ireland population, served by a single paediatric cardiology centre, we determine the prevalence and trends of CHD among live births. METHODS: This is a descriptive cross-sectional population-based study, using the paediatric cardiology database. The study included a total of 245,120 live births representing all children born in Northern Ireland 2005-2014. RESULTS: A total of 11,410 children (4.65% of live births in Northern Ireland) received an echocardiogram for suspected CHD, and 3,059 children were subsequently diagnosed with a major CHD (prevalence = 12.48 per 1,000 live births (95% CI 12.04-12.93)) of whom 490 (16.02%) had genetic or chromosomal disorders including Down syndrome. The prevalence of non-genetic or chromosomal cases was 10.48 per 1,000 live births (95% CI 10.08-10.89) and did not change significantly over time (p = 0.91). The prevalence of CHD diagnosed in the first year of life was 8.46 per 1,000 live births (95% CI 8.10-8.83), which increased over time (p < 0.01). The prevalence of severe CHD was 2.02 per 1,000 live births (95% CI 1.85-2.21). CONCLUSION: Northern Ireland has a high prevalence of CHD among European countries, which may be associated with complete ascertainment of both early and late diagnosed cases recorded in the paediatric cardiology database, as well as being one of the few European countries where terminations of pregnancy for foetal anomaly was illegal during the study period.

Neurodevelopmental and psychosocial interventions for individuals with CHD: a research agenda and recommendations from the Cardiac Neurodevelopmental Outcome Collaborative.

In 2018, the Neurodevelopmental and Psychosocial Interventions Working Group of the Cardiac Neurodevelopmental Outcome Collaborative convened through support from an R13 grant from the National Heart, Lung, and Blood Institute to survey the state of neurodevelopmental and psychosocial intervention research in CHD and to propose a slate of critical questions and investigations required to improve outcomes for this growing population of survivors and their families. Prior research, although limited, suggests that individualised developmental care interventions delivered early in life are beneficial for improving a range of outcomes including feeding, motor and cognitive development, and physiological regulation. Interventions to address self-regulatory, cognitive, and social-emotional challenges have shown promise in other medical populations, yet their applicability and effectiveness for use in individuals with CHD have not been examined. To move this field of research forward, we must strive to better understand the impact of neurodevelopmental and psychosocial intervention within the CHD population including adapting existing interventions for individuals with CHD. We must examine the ways in which dedicated cardiac neurodevelopmental follow-up programmes bolster resilience and support children and families through the myriad transitions inherent to the experience of living with CHD. And, we must ensure that interventions are person-/family-centred, inclusive of individuals from diverse cultural backgrounds as well as those with genetic/medical comorbidities, and proactive in their efforts to include individuals who are at highest risk but who may be traditionally less likely to participate in intervention trials.

The CHIP-Family study to improve the psychosocial wellbeing of young children with congenital heart disease and their families: design of a randomized controlled trial.

BACKGROUND: Children with congenital heart disease (CHD) are at increased risk for behavioral, emotional, and cognitive problems. They often have reduced exercise capacity and participate less in sports, which is associated with a lower quality of life. Starting school may present more challenges for children with CHD and their families than for families with healthy children. Moreover, parents of children with CHD are at risk for psychosocial problems. Therefore, a family-centered psychosocial intervention for children with CHD when starting school is needed. Until now, the 'Congenital Heart Disease Intervention Program (CHIP) - School' is the only evidence-based intervention in this field. However, CHIP-School targeted parents only and resulted in non-significant, though positive, effects as to child psychosocial wellbeing. Hence, we expanded CHIP by adding a specific child module and including siblings, creating the CHIP-Family intervention. The CHIP-Family study aims to (1) test the effects of CHIP-Family on parental mental health and psychosocial wellbeing of CHD-children and to (2) identify baseline psychosocial and medical predictors for the effectiveness of CHIP-Family. METHODS: We will conduct a single-blinded randomized controlled trial comparing the effects of CHIP-Family with care as usual (no psychosocial intervention). Children with CHD (4-7 years old) who are starting or attending kindergarten or primary school (first or second year) at the time of first assessment and their families are eligible. CHIP-Family consists of a separate one-day workshop for parents and children. The child workshop consists of psychological exercises based on the evidence-based cognitive behavioral therapy Fun FRIENDS protocol and sports exercises. The parent workshop focuses on problem prevention therapy, psychoeducation, general parenting skills, skills specific to parenting a child with CHD, and medical issues. Approximately 4 weeks after the workshop, parents receive an individual follow-up session. The baseline (T1) and follow-up assessment (T2 = 6 months after T1) consist of online questionnaires filled out by the child, parents, and teacher (T2 only). Primary outcome measures are the CBCL for children and the SCL-90-R for parents. DISCUSSION: This trial aims to test the effects of an early family-centered psychosocial intervention to meet the compelling need of young children with CHD and their families to prevent (further) problems. If CHIP-Family proves to be effective, it should be structurally implemented in standard care. TRIAL REGISTRATION: Dutch Trial Registry; NTR6063 on 23 August, 2016.

Multidisciplinary family-centred psychosocial care for patients with CHD: consensus recommendations from the AEPC Psychosocial Working Group.

Because of the enormous advances in the medical treatment of CHD, the long-term survival of patients suffering from this disease has increased significantly. Currently, about 90% of patients reach adulthood, which entails many new challenges both for patients and their families and for healthcare professionals. The main objective of family-centred psychosocial care is to strengthen the emotional resilience of chronically ill patients and their families by adopting a holistic approach. During the biannual meeting of the psychosocial working group in 2012, participants expressed the need for general European guidelines. The present recommendations were written to support medical staff and psychosocial healthcare professionals to provide the best care for children and adolescents with CHD as well as for their families. This article describes in detail how the integrated family-centred psychological care modules work, involving different healthcare specialists, including a paediatric/congenital cardiologist or a general paediatrician. The different clinical implications and specific needs have been taken into account and recommendations have been provided on the following: structured follow-up screening; identification of stressful periods related to cardiac surgery or invasive medical procedures; evidence-based, disease-specific, and family-oriented psychosocial interventions; and interactive media links to medical and psychosocial information.

Survey of paediatricians' opinions on a regional paediatric telecardiology service.

AIM: The aim of this study is to evaluate consultant general paediatricians' opinions of a UK paediatric telecardiology service. METHODS: A structured questionnaire was developed and sent to all consultant paediatricians working in a district general hospital in Northern Ireland. RESULTS: Paediatricians (n = 35) regarded the regional paediatric telecardiology service as very useful and of good value for money. Paediatricans in hospitals without access to telecardiology expressed a desire to join the network (86%, 12/14). More frequent use of the paediatric telecardiology service was associated with increased confidence in performing echocardiography and using the telemedicine equipment and a special interest in neonatology. The vast majority of paediatricians (32/35, 91%) believed that there should be a shared clinical responsibility for the patient following a teleconsultation. A total of 33/35 (94%) stated that the telephone costs of the consultation should be paid by the paediatrician but that the professional time of the cardiologist should be paid by the tertiary centre (29/35, 83%). CONCLUSIONS: Paediatricians have consistently positive experiences of a regional paediatric telecardiology service. They believe that clinical responsibility is shared, and there should not be any professional fee for telemedicine activities.

Epicardial Pacemaker Causing Cardiac Strangulation.

Cardiac strangulation is a rare but potentially lethal complication of epicardial pacemaker insertion. We present the case of a 9-year-old girl who was identified as having cardiac strangulation on routine follow-up for an epicardial pacemaker inserted on day 1 of life for congenital complete heart block (CCHB). The potential clinical presentations and risk factors for pacemaker strangulation are then discussed.

A sibling-controlled, prospective study of outcomes at home and school in children with severe congenital heart disease.

OBJECTIVES: The objectives of this study were to compare behaviour problems and competencies, at home and school, in 7-year-old children with congenital heart disease with a sibling control group, to examine the prospective determinants of outcome from infancy, and to explore whether any gains were maintained in our sub-group of children who had participated in a previous trial of psychological interventions in infancy. METHODS: A total of 40 children who had undergone surgery to correct or palliate a significant congenital heart defect in infancy were compared (Child Behavior Checklist) with a nearest-age sibling control group (18 participants). Comparisons were made between sub-groups of children and families who had and had not participated in an early intervention trial. RESULTS: Problems with attention, thought and social problems, and limitations in activity and school competencies, were found in comparison with siblings. Teacher reports were consistent with parents, although problems were of a lower magnitude. Disease, surgical, and neurodevelopmental functioning in infancy were related to competence outcomes but not behaviour problems. The latter were mediated by family and maternal mental health profiles from infancy. Limited, but encouraging, gains were maintained in the sub-group that had participated in the early intervention programme. CONCLUSIONS: The present study is strengthened by its longitudinal design, use of teacher informants, and sibling control group. The patterns of problems and limitations discerned, and differential determinants thereof, have clear implications for interventions. We consider these in the light of our previously reported intervention trial with this sample and current outcomes at the 7-year follow-up.

A randomized controlled trial of interventions to promote adjustment in children with congenital heart disease entering school and their families.

OBJECTIVE: To report on a randomized controlled trial of psychological interventions to promote adjustment in children with congenital heart disease and their families. METHOD: Following baseline assessment, 90 children (aged 4-5 years) and their families were randomly assigned to an Intervention or Control group before entering school. 68 (76%) were retained at 10-month follow-up. RESULTS: Gains were observed on measures of maternal mental health and family functioning. Although no differences were found on measures of child behavior at home or school, children in the intervention group were perceived as "sick" less often by their mother and missed fewer days from school. A regression model, using baseline measures as predictors, highlighted the importance of maternal mental health, worry and child neurodevelopmental functioning for child behavioral outcomes almost a year later. CONCLUSIONS: The intervention promoted clinically significant gains for the child and family. The program is of generalizable significance.

A fetal telecardiology service: patient preference and socio-economic factors.

OBJECTIVE: The aims of this study were to evaluate patients' opinions on a fetal cardiology telemedicine service compared with usual outpatient care, the effect of the telemedicine consultation on maternal anxiety and its impact on travel times and time absent from work. METHODS: Prospective study over 20 months. Eligible patients attended for routine anomaly scan followed by fetal echocardiogram transmitted to the regional centre with live guidance by a fetal cardiologist, followed by parental counselling. All patients were offered a fetal cardiology appointment at the regional centre. Structured questionnaires assessing maternal satisfaction, travel times/days off and anxiety scores completed at time of both fetal echocardiograms. RESULTS: Sixty-seven patients were recruited and 66 completed the study. Participants expressed very high satisfaction rates with fetal telecardiology, equivalent to face-to-face consultation. The telecardiology appointments were associated with significantly reduced travel times and days off work (p < 0.01). Expectant mothers expressed a clear inclination for a fetal cardiology appointment at the local hospital facilitated by telemedicine (p < 0.01). CONCLUSIONS: Fetal telecardiology is highly acceptable to patients and is even preferred compared with travelling to a regional centre. There are additional socio-economic benefits that should encourage the development of remote fetal cardiology services.

Editorial Board Composition Among Pediatric Cardiology Journals: Time to Cast the Net Wider.

Background: No data currently exist on the diversity of editorial board members (EBMs) of pediatric cardiology journals. Objectives: The objective was to investigate the editorial boards of 5 pediatric cardiology journals to assess the composition of these boards in terms of the geographical, gender, and economic representation of their members. Methods: Information on EBMs was collected directly from 5 journal websites accessed in February 2022. The following data were collected: country of practice (including World Bank geographical and income classification), institution of practice, role on editorial board, and whether an individual held a role on 1 or more of the boards included. Results: A total of 455 EBMs were identified. A total of 369 (81%) were male. All editors-in-chief were male, and 4 were from the United States. EBMs practicing in North America accounted for 278 individuals (61%) of the editorial boards reviewed. The next majority of EBMs are practicing within Europe and Central Asia (23%, n = 103), East Asia and Pacific (7%, n = 31), Middle East and North Africa (4%, n = 18), and Latin America and Caribbean (4%, n = 16). Less than 2% (n = 9) practice in Sub-Saharan Africa and South Asia. Over 90% (n = 415) practice in high-income countries. There was no representation from low-income countries. Conclusions: Women and pediatric cardiologists practicing in countries outside of Europe and North America were underrepresented on the editorial boards of the journals studied. Diversifying composition of editorial boards may provide greater representation of underserved areas and encourage broader avenues of investigation and research.

MG132 Induces Progerin Clearance and Improves Disease Phenotypes in HGPS-like Patients' Cells.

Progeroid syndromes (PS), including Hutchinson-Gilford Progeria Syndrome (HGPS), are premature and accelerated aging diseases, characterized by clinical features mimicking physiological aging. Most classical HGPS patients carry a de novo point mutation within exon 11 of the LMNA gene encoding A-type lamins. This mutation activates a cryptic splice site, leading to the production of a truncated prelamin A, called prelamin A ∆50 or progerin, that accumulates in HGPS cell nuclei and is a hallmark of the disease. Some patients with PS carry other LMNA mutations and are named "HGPS-like" patients. They produce progerin and/or other truncated prelamin A isoforms (∆35 and ∆90). We previously found that MG132, a proteasome inhibitor, induced progerin clearance in classical HGPS through autophagy activation and splicing regulation. Here, we show that MG132 induces aberrant prelamin A clearance and improves cellular phenotypes in HGPS-like patients' cells other than those previously described in classical HGPS. These results provide preclinical proof of principle for the use of a promising class of molecules toward a potential therapy for children with HGPS-like or classical HGPS.

Exercise prescription improves exercise tolerance in young children with CHD: a randomised clinical trial.

OBJECTIVE: The main objective of this study was to ascertain if a structured intervention programme can improve the biophysical health of young children with congenital heart disease (CHD). The primary end point was an increase in measureable physical activity levels following the intervention. METHODS: Patients aged 5-10 years with CHD were identified and invited to participate. Participants completed a baseline biophysical assessment, including a formal exercise stress test and daily activity monitoring using an accelerometer. Following randomisation, the intervention group attended a 1 day education session and received an individual written exercise plan to be continued over the 4-month intervention period. The control group continued with their usual level of care. After 4 months, all participants were reassessed in the same manner as at baseline. RESULTS: One hundred and sixty-three participants (mean age 8.4 years) were recruited, 100 of whom were male (61.3%). At baseline, the majority of the children were active with good exercise tolerance. The cyanotic palliated subgroup participants, however, were found to have lower levels of daily activity and significantly limited peak exercise performance compared with the other subgroups. One hundred and fifty-two participants (93.2%) attended for reassessment. Following the intervention, there was a significant improvement in peak exercise capacity in the intervention group. There was also a trend towards increased daily activity levels. CONCLUSION: Overall physical activity levels are well preserved in the majority of young children with CHD. A structured intervention programme significantly increased peak exercise capacity and improved attitudes towards positive lifestyle changes.

Examination of the physical and psychosocial determinants of health behaviour in 4-5-year-old children with congenital cardiac disease.

OBJECTIVES: To assess the general health and activity levels of 4- and 5-year-old children after intervention for congenital cardiac disease. METHODS: Health behaviour outcomes were assessed in 91 children who had surgery or catheter intervention for congenital cardiac disease. The children were classified into four groups according to severity. The main parameters of classification were the presence of residual symptoms, frequency of visits to general practitioner or the Accident and Emergency Department, and ability to participate in physical activity according to a calculated "activity score". RESULTS: Children had very few residual symptoms after "corrective surgery". Those with complex congenital cardiac disease post-Fontan-type repair still had symptoms on average 18.2 days per month. Surprisingly, the complex group had fewer days "sick" from non-cardiac causes and had fewer visits to general practitioner or Accident and Emergency Departments. Regression analysis indicates that three variables had significant relevance to the general practitioner or Accident and Emergency visits: complex congenital cardiac disease, fewer visits; Townsend score - more deprivation - more visits; and maternal worry - higher maternal worry score - more visits. Regression analysis indicates that lower activity score is significantly related to complex cardiac disease and higher maternal worry score. CONCLUSIONS: The majority of this group of 4- and 5-year-old children had few residual symptoms and had good exercise tolerance. Maternal worry is a significant factor in influencing both activity levels and frequency of unscheduled health service demands - general practitioner or Accident and Emergency visits.

Risk factors for congenital heart disease: The Baby Hearts Study, a population-based case-control study.

We investigated the role of maternal environmental factors in the aetiology of congenital heart disease (CHD). A population-based case-control study (242 CHD cases, 966 controls) was conducted using an iPad questionnaire for mother with linkage to maternity and first trimester prescription records. Risk of CHD was associated with low maternal education (OR adjusted for confounders 1.59; 95% confidence interval [CI], 1.02-2.49), pregestational diabetes (OR 4.04; 95% CI 1.00-16.28), self-reported maternal clotting disorders (adjOR 8.55, 95%CI 1.51-48.44), prescriptions for the anticlotting medication enoxaparin (adjOR 3.22, 95%CI 1.01-10.22) and self-reported vaginal infections (adjOR 1.69, 95%CI 1.01-2.80). There was no strong support for the hypothesis that periconceptional folic acid supplements have a protective effect, but there was a protective effect of frequent consumption of folate rich fruits (adjOR 0.64, 95%CI 0.47-0.89). Compared to the most common pre-pregnancy dietary pattern, CHD risk was associated with a poor diet low in fruit and vegetables (adjOR 1.56, 95%CI 1.05-2.34). Mothers of cases reported more pregnancy related stress (adjOR 1.69; 95% CI 1.22-2.34) and multiple stressors (adjOR 1.94, 95%CI 0.83-4.53). We found no supportive evidence for CHD risk being associated with obesity, smoking, depression or antidepressant use in this population. Our findings add to the previous evidence base to show potential for public health approaches to help prevent CHD in future by modifying environmental factors. Independent confirmation should be sought regarding elevated CHD risk associated with maternal blood clotting disorders and their treatment, since we are the first to report this.

Neurodevelopmental Outcomes Among Children With Congenital Heart Disease: At-Risk Populations and Modifiable Risk Factors.

As survivable outcomes among patients with complex congenital heart disease (cCHD) have continued to improve over the last several decades, more attention is being dedicated to interventions that impact not just survival but quality of life among patients with cCHD. In particular, patients with cCHD are at risk for impaired neurodevelopmental outcomes. In this review summarizing select presentations given at the 14th Annual Pediatric Cardiac Intensive Care Society's Annual Meeting in 2019, we discuss the neurodevelopmental phenotype of patients with cCHD, patients at greatest risk of impaired development, and three specific modifiable risk factors impacting development.

32 year follow up of patients following atrial redirection surgery for transposition of the great arteries.

OBJECTIVE: A significant body of patients who have undergone Mustard or Senning procedure require lifelong follow up. In this retrospective review, we examined the cohort of such patients currently attending our center. DESIGN: Patients who had undergone either Mustard or Senning procedure were identified. We retrospectively reviewed medical records, recorded demographic information and data regarding the clinical state, NHYA class, cardiopulmonary exercise testing, NT-proBNP measurement, and recent cardiac MRI findings. RESULTS: Forty-six patients were identified, the mean age was 32.2 years (± 6.1 years), 67.4% were male. Thirty-two patients (69.6%) had undergone a Senning procedure. The median length of the follow-up was 32 years. Thirty-two patients (69.6%) were NHYA class 1. The mean VO2max achieved was 24.2 ± 5.8 mL/min/kg. The mean NT-proBNP was 266.4 pg/mL (± 259.9 pg/mL). The mean right ventricular end-diastolic volume (RVEDV) was 212.4 mL ± 73.1 mL (indexed 114.2 mL/m2  ± 34.4 mL/m2 ). The mean right ventricular ejection fraction (RVEF) was 53.7% ± 7.9%. The mean left ventricular end-diastolic volume (LVEDV) was 161.5 mL ± 73.7 mL (indexed 87.8 mL/m2  ± 41.1 mL/m2 ). The mean left ventricular ejection fraction (LVEF) was 59.8% ± 5.7%. There was a significant correlation between right ventricular (RV) size on MRI and NT-proBNP level. CONCLUSIONS: We present a relatively well cohort of patients with overall favorable long-term outcome. The majority of patients are NHYA class 1 and the systemic right ventricular function appears to be well preserved as assessed by MRI. The exercise tolerance is reduced, with the majority of patients achieving around 60% of the estimated VO2max . Regular specialist follow-up and assessment with advanced imaging at regular intervals remain important for this group.