Altered Inflammatory State and Mitochondrial Function Identified by Transcriptomics in Paediatric Congenital Heart Patients Prior to Surgical Repair.

Congenital heart disease (CHD) remains the most common birth defect, with surgical intervention required in complex cases. Right ventricle (RV) function is known to be a major predictor of sustained cardiac health in these patients; thus, by elucidating the divergent profiles between CHD and the control through tissue analysis, this study aims to identify new avenues of investigation into the mechanisms surrounding reduced RV function. Transcriptomic profiling, in-silico deconvolution and functional network analysis were conducted on RV biopsies, identifying an increase in the mitochondrial dysfunction genes RPPH1 and RMPR (padj = 4.67 × 10-132, 2.23 × 10-107), the cytotoxic T-cell markers CD8a, LAGE3 and CD49a (p = 0.0006, p < 0.0001, and p = 0.0118) and proinflammatory caspase-1 (p = 0.0055) in CHD. Gene-set enrichment identified mitochondrial dysfunctional pathways, predominately changes within oxidative phosphorylation processes. The negative regulation of mitochondrial functions and metabolism was identified in the network analysis, with dysregulation of the mitochondrial complex formation. A histological analysis confirmed an increase in cellular bodies in the CHD RV tissue and positive staining for both CD45 and CD8, which was absent in the control. The deconvolution of bulk RNAseq data suggests a reduction in CD4+ T cells (p = 0.0067) and an increase in CD8+ T cells (p = 0.0223). The network analysis identified positive regulation of the immune system and cytokine signalling clusters in the inflammation functional network, as there were lymphocyte activation and leukocyte differentiation. Utilising RV tissue from paediatric patients undergoing CHD cardiac surgery, this study identifies dysfunctional mitochondrial pathways and an increase in inflammatory T-cell presence prior to reparative surgery.

Plasma metabolomic and lipidomic profiles accurately classify mothers of children with congenital heart disease: an observational study.

INTRODUCTION: Congenital heart disease (CHD) is the most common congenital anomaly, representing a significant global disease burden. Limitations exist in our understanding of aetiology, diagnostic methodology and screening, with metabolomics offering promise in addressing these. OBJECTIVE: To evaluate maternal metabolomics and lipidomics in prediction and risk factor identification for childhood CHD. METHODS: We performed an observational study in mothers of children with CHD following pregnancy, using untargeted plasma metabolomics and lipidomics by ultrahigh performance liquid chromatography-high resolution mass spectrometry (UHPLC-HRMS). 190 cases (157 mothers of children with structural CHD (sCHD); 33 mothers of children with genetic CHD (gCHD)) from the children OMACp cohort and 162 controls from the ALSPAC cohort were analysed. CHD diagnoses were stratified by severity and clinical classifications. Univariate, exploratory and supervised chemometric methods were used to identify metabolites and lipids distinguishing cases and controls, alongside predictive modelling. RESULTS: 499 metabolites and lipids were annotated and used to build PLS-DA and SO-CovSel-LDA predictive models to accurately distinguish sCHD and control groups. The best performing model had an sCHD test set mean accuracy of 94.74% (sCHD test group sensitivity 93.33%; specificity 96.00%) utilising only 11 analytes. Similar test performances were seen for gCHD. Across best performing models, 37 analytes contributed to performance including amino acids, lipids, and nucleotides. CONCLUSIONS: Here, maternal metabolomic and lipidomic analysis has facilitated the development of sensitive risk prediction models classifying mothers of children with CHD. Metabolites and lipids identified offer promise for maternal risk factor profiling, and understanding of CHD pathogenesis in the future.

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).

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.

Prospective multiparametric CMR characterization and MicroRNA profiling of anthracycline cardiotoxicity: A pilot translational study.

Background: Anthracycline cardiotoxicity is a significant clinical challenge. Biomarkers to improve risk stratification and identify early cardiac injury are required. Objectives: The purpose of this pilot study was to prospectively characterize anthracycline cardiotoxicity using cardiovascular magnetic resonance (CMR), echocardiography and MicroRNAs (MiRNAs), and identify baseline predictors of LVEF recovery. Methods: Twenty-four patients (age 56 range 18-75 years; 42 % female) with haematological malignancy scheduled to receive anthracycline chemotherapy (median dose 272 mg/m2 doxorubicin equivalent) were recruited and evaluated at three timepoints (baseline, completion of chemotherapy, and 6 months after completion of chemotherapy) with multiparametric 1.5 T CMR, echocardiography and circulating miRNAs sequencing. Results: Seventeen complete datasets were obtained. CMR left ventricular ejection fraction (LVEF) fell significantly between baseline and completion of chemotherapy (61 ± 3 vs 53 ± 3 %, p < 0.001), before recovering significantly at 6-month follow-up (55 ± 3 %, p = 0.018). Similar results were observed for 3D echocardiography-derived LVEF and CMR-derived longitudinal, circumferential and radial feature-tracking strain. Patients were divided into tertiles according to LVEF recovery (poor recovery, partial recovery, good recovery). CMR-derived mitral annular plane systolic excursion (MAPSE) was significantly different at baseline in patients exhibiting poor LVEF recovery (11.7 ± 1.5 mm) in comparison to partial recovery (13.7 ± 2.7 mm), and good recovery (15.7 ± 3.1 mm; p = 0.028). Furthermore, baseline miRNA-181-5p and miRNA-221-3p expression were significantly higher in this group. T2 mapping increased significantly on completion of chemotherapy compared to baseline (54.0 ± 4.6 to 57.8 ± 4.9 ms, p = 0.001), but was not predictive of LVEF recovery. No changes to LV mass, extracellular volume fraction, T1 mapping or late gadolinium enhancement were observed. Conclusions: Baseline CMR-derived MAPSE, circulating miRNA-181-5p, and miRNA-221-3p were associated with poor recovery of LVEF 6 months after completion of anthracycline chemotherapy, suggesting their potential predictive role in this context. T2 mapping increased significantly on completion of chemotherapy but was not predictive of LVEF recovery.

Factors affecting decision-making in children with complex care needs: a consensus approach to develop best practice in a UK children's hospital.

BACKGROUND: Children with complex care needs are a growing proportion of the sick children seen in all healthcare settings in the UK. Complex care needs place demands on parents and professionals who often require many different healthcare teams to work together. Care can be both materially and logistically difficult to manage, causing friction with parents. These difficulties may be reduced if common best practice standards and approaches can be developed in this area. OBJECTIVE: To develop a consensus approach to the management of complexity among healthcare professionals, we used a modified Delphi process. The process consisted of a meeting of clinical leaders to develop candidate statements, followed by two survey rounds open to all professionals in a UK children's hospital to measure and establish consensus recommendations. RESULTS: Ninety-nine professionals completed both rounds of the survey, 69 statements were agreed. These pertained to seven thematic areas: standardised approaches to communicating with families; processes for interprofessional communication; processes for shared decision-making in the child's best interests; role of the multidisciplinary team; managing professional-parental disagreement and conflict; the role of clinical psychologists; and staff support. Overall, the level of consensus was high, ranging from agreement to strong agreement. CONCLUSIONS: These statements provide a consensus basis that can inform standardised approaches to the management of complexity. Such approaches may decrease friction between parents, children and healthcare professionals.

Surgical-PEARL protocol: a multicentre prospective cohort study exploring aetiology, management and outcomes for patients with congenital anomalies potentially requiring surgical intervention.

INTRODUCTION: Congenital anomalies affect over 2% of pregnancies. Surgical advances have reduced mortality and improved survival for patients with congenital anomalies potentially requiring surgical (CAPRS) intervention. However, our understanding of aetiology, diagnostic methods, optimal management, outcomes and prognostication is limited. Existing birth cohorts have low numbers of individual heterogenous CAPRS. The Surgical Paediatric congEnital Anomalies Registry with Long term follow-up (Surgical-PEARL) study aims to establish a multicentre prospective fetal, child and biological parent cohort of CAPRS. METHODS AND ANALYSIS: From 2022 to 2027, Surgical-PEARL aims to recruit 2500 patients with CAPRS alongside their biological mothers and fathers from up to 15 UK centres. Recruitment will be antenatal or postnatal dependent on diagnosis timing and presentation to a recruitment site. Routine clinical data including antenatal scans and records, neonatal intensive care unit (NICU) records, diagnostic and surgical data and hospital episode statistics will be collected. A detailed biobank of samples will include: parents' blood and urine samples; amniotic fluid if available; children's blood and urine samples on admission to NICU, perioperatively or if the child has care withdrawn or is transferred for extracorporeal membrane oxygenation; stool samples; and surplus surgical tissue. Parents will complete questionnaires including sociodemographic and health data. Follow-up outcome and questionnaire data will be collected for 5 years. Once established we will explore the potential of comparing findings in Surgical-PEARL to general population cohorts born in the same years and centres. ETHICS AND DISSEMINATION: Ethical and health research authority approvals have been granted (IRAS Project ID: 302251; REC reference number 22/SS/0004). Surgical-PEARL is adopted onto the National Institute for Health Research Clinical Research Network portfolio. Findings will be disseminated widely through peer-reviewed publication, conference presentations and through patient organisations and newsletters. TRIAL REGISTRATION NUMBER: ISRCTN12557586.

Determinants of QRS duration in patients with tetralogy of Fallot after pulmonary valve replacement.

BACKGROUND: Following the repair of TOF patients may be left with pulmonary regurgitation and a dilated right ventricle (RV), which in turn can lead to ventricular arrhythmias and sudden death. A prolonged QRS is a predictor of ventricular arrhythmias. However, whether subsequent pulmonary valve replacement (PVR) can reverse QRS-prolongation is controversial. We hypothesized that changes in QRS duration following PVR are determined by preoperative QRS-duration and RV volumes METHODS: A retrospective single-center cohort study was conducted on 142 post-TOF repair patients (mean age 25 ± 13 years) who underwent PVR between 1995 and 2019. Information on QRS duration and RV volumes measured by cardiac MRI (available in 83 patients) were collected. A linear mixed model was used to investigate the association between the preoperative QRS duration and RV volumes and the postoperative QRS duration. RESULTS: The QRS-duration following PVR continued to increase in all subjects with a prolonged preoperative QRS-duration(>160 ms, rate of increase of 0.87 msec ± 0.33 per year; p = .01), markedly raised RV end-diastolic volume (RVEDV; ≥166 ml/m2, rate of increase of 2.0 msec ± 0.37 per year; p < .01) or RV end-systolic volume (RVESV; ≥89 ml/m2 , rate of increase of 1.25 msec ± 0.43 per year; p = .01). In contrast, in patients with preoperative QRS-duration <160 msec (p = .16), RVEDV <166 ml/m2 (p = .14), or RVESV < 89 ml/m2 (p = .37), the QRS-duration did not change significantly when compared to preoperative values. CONCLUSIONS: In subjects with shorter QRS and smaller RV volumes, QRS duration did not show further prolongation following PVR. While markedly prolonged QRS and increased RV volumes were associated with a small but constant increase in QRS duration despite PVR.

COVID-19, State of the Adult and Pediatric Heart: From Myocardial Injury to Cardiac Effect of Potential Therapeutic Intervention.

While the COVID-19 pandemic continues to spread rapidly, resulting in considerable morbidity and mortality worldwide, multiple efforts are being made by the international scientific community to understand the pathogenesis of the viral infection and its clinical outcome. Older age and comorbidities have consistently been reported as risk factors for unfavorable prognosis, with cardiovascular disease accounting for up to 10 % of comorbid conditions among the infected patients. An understanding of the mechanism underlying the effect of this infection on patients with cardiovascular disease is essential to manage and improve clinical strategies against the disease in that population. In this review, we summarize the impact of COVID-19 on patients with underlying cardiovascular conditions and the cardiac implications of known and emerging therapeutic strategies. Our future effort will aim to further elucidate how the type and severity of the cardiac disease, with particular regard to Congenital Heart Disease, influences the prognosis and the outcome of the viral infection.

Long-Term Comparison Between Pulmonary Homograft Versus Bioprosthesis for Pulmonary Valve Replacement in Tetralogy of Fallot.

Background Tetralogy of Fallot repair results in late occurrence of pulmonary regurgitation, which requires pulmonary valve replacement in a large proportion of patients. Both homografts and bioprostheses are used for pulmonary valve replacement as uncertainty remains on which prosthesis should be considered superior. We performed a long-term imaging and clinical comparison between these 2 strategies. Methods and Results We compared echocardiographic and clinical follow-up data of 209 patients with previous tetralogy of Fallot repair who underwent pulmonary valve replacement with homograft (n=75) or bioprosthesis (n=134) between 1995 and 2018 at a tertiary hospital. The primary end point was the composite of pulmonary valve replacement reintervention and structural valve deterioration, defined as a transpulmonary pressure decrease ≥50 mm Hg or pulmonary regurgitation degree of ≥2. Mixed linear model and Cox regression model were used for comparisons. Echocardiographic follow-up duration was longer in the homograft group (8 [interquartile range, 4-12] versus 4 [interquartile range, 3-6] years; P<0.001). At the latest echocardiographic follow-up, homografts showed a significantly lower transpulmonary systolic pressure decrease (16 [interquartile range, 12-25] mm Hg) when compared with bioprostheses (28 [interquartile range, 18-41] mm Hg; mixed model P<0.001) and a similar degree of pulmonary regurgitation (degree 0-4) (1 [interquartile range, 0-2] versus 2 [interquartile range, 0-2]; mixed model P=0.19). At 9 years, freedom from structural valve deterioration and reintervention was 81.6% (95% CI, 71.5%-91.6%) versus 43.4% (95% CI, 23.6%-63.2%) in the homograft and bioprosthesis groups, respectively (adjusted hazard ratio, 0.27; 95% CI, 0.13-0.55; P<0.001). Conclusions When compared with bioprostheses, pulmonary homografts were associated lower transvalvular gradient during follow-up and were associated with a significantly lower risk of reintervention or structural valve degeneration.

Determinants of aortic growth rate in patients with bicuspid aortic valve by cardiovascular magnetic resonance.

Objectives: This study aimed to identify determinants of aortic growth rate in bicuspid aortic valve (BAV) patients. We hypothesised that (1) BAV patients with repaired coarctation (CoA) exhibit decreased aortic growth rate, (2) moderate/severe re-coarctation (reCoA) results in increased growth rate, (3) patients with right non-coronary (RN) valve cusps fusion pattern exhibit increased aortic growth rate compared with right-left cusps fusion and type 0 valves. Methods: Starting from n=521 BAV patients with cardiovascular magnetic resonance data, we identified n=145 patients with at least two scans for aortic growth analysis. Indexed areas of the sinuses of Valsalva and ascending aorta (AAo) were calculated from cine images in end-systole and end-diastole. Patients were classified based on dilation phenotype, presence of CoA, aortic valve function and BAV morphotype. Comparisons between groups were performed. Linear regression was carried out to identify associations between risk factors and aortic growth rate. Results: Patients (39±16 years of age, 68% male) had scans 3.7±1.8 years apart; 32 presented with AAo dilation, 18 with aortic root dilation and 32 were overall dilated. Patients with repaired CoA (n=61) showed decreased aortic root growth rate compared with patients without CoA (p≤0.03) regardless of sex or age. ReCoA, aortic stenosis, regurgitation and history of hypertension were not associated with growth rate. RN fusion pattern showed the highest aortic root growth rate and type 0 the smallest (0.30 vs 0.08 cm2/m*year, end-systole, p=0.03). Conclusions: Presence of CoA and cusp fusion morphotype were associated with changes in rate of root dilation in our BAV population.