Background Heart failure (HF) is underdiagnosed in the community. N-terminal pro-B-type natriuretic peptide (NT-proBNP) has variable sensitivity for HF across different subgroups, particularly for HF with preserved ejection fraction (HFpEF). We calculated individualised NT-proBNP thresholds with 90% sensitivity for the detection of HF, adjusted for age and comorbidities. We investigated whether individualised thresholds had greater sensitivity for the detection of HF, and whether adverse event rates were similarly low in patients with NT-proBNP levels below individualised and fixed thresholds. Methods A total of 1320 patients were recruited from a prospective clinical cohort referred for cardiovascular magnetic resonance (CMR). The diagnostic performance of individualised and fixed NT-proBNP thresholds for detecting HF was compared. The associations between individualised thresholds and the primary composite outcome of first HF hospitalisation or cardiovascular death were investigated. Results Individualised NT-proBNP thresholds ranged from 31 to 2295 pg/ml. Individualised thresholds were more sensitive for the detection of all HF (0.90; 0.80 for 125 pg/ml; 0.55 for 400 pg/ml), HFpEF (0.87; 0.74 for 125 pg/ml; 0.43 for 400 pg/ml), and HF with reduced ejection fraction (0.98; 0.94 for 125 pg/ml; 0.83 for 400 pg/ml) and achieved a high sensitivity of ~0.90 in all patient subgroups. Individualised thresholds associated with adverse outcomes (hazard ratio and 95% confidence interval 6.88 (3.04-15.60)). Patients with NT-proBNP levels below individualised thresholds and a fixed threshold of 125 pg/ml had similarly low event rates. Conclusions Individualised NT-proBNP thresholds, optimised for increased sensitivity, may inform future investigation in community settings.

Abstract Background Pericardial adipose tissue (PAT) has been associated with adverse cardiac remodelling and incident heart failure (HF),[1] potentially through promotion of myocardial fibrosis, but supporting clinical data remain limited. Purpose In patients at risk of HF, we investigated the associations between PAT area, cardiovascular magnetic resonance (CMR)-derived measures of myocardial fibrosis (extracellular volume (ECV) and native T1), and adverse cardiovascular outcomes, independent of confounders including body mass index (BMI). Methods A total of 2,038 patients at risk of HF were enrolled from a prospective cohort undergoing clinically indicated CMR. Imaging included pre- and post-contrast T1 mapping with same-day haematocrit to measure myocardial ECV. PAT area was quantified at end-diastole from four-chamber cine images using an automated algorithm.[2] Exclusion criteria included hypertrophic or infiltrative cardiomyopathies, congenital heart disease, prior HF hospitalisation, or normal cardiac structure and function without cardiovascular risk factors. Outcome data were obtained from Hospital Episode Statistics ICD-10 codes. The primary composite outcome was time to first HF hospitalisation or cardiovascular (CV) death. Linear and Cox proportional hazards regression were used to assess associations between PAT area, myocardial fibrosis markers, and adverse outcomes. Multivariable models were adjusted for baseline demographics, comorbidities, and CMR measures of cardiac structure and function. Results Baseline characteristics are shown in Figure 1A. Greater PAT area and higher BMI were independently associated with lower myocardial ECV, an association observed only in patients with left ventricular ejection fraction (LVEF) ≥40% (Figure 1B). No significant association was found between PAT area and native T1, regardless of LVEF (ß -0.01, 95% CI -0.03 – 0.01, p=0.27). During a median follow-up of 2,676 days (IQR 2,500 – 2,891), the primary outcome occurred in 166 (8%) patients. PAT area was associated with the primary outcome on univariate analysis (Figure 2A). After multivariable adjustment, BMI, but not PAT area, remained independently associated with the primary outcome (Figure 2B), driven by HF hospitalisation (HR 1.56, 95% CI 1.25 – 1.94, p<0.001) rather than CV death (HR 1.04, 95% CI 0.81 – 1.34, p=0.75). Conclusions Pericardial adipose tissue does not appear to exert deleterious cardiovascular effects via myocardial fibrosis. Further, after comprehensive multivariable adjustment with deep phenotyping, pericardial fat was not independently predictive of adverse cardiovascular outcomes.For image description, please refer to the figure legend and surrounding text.For image description, please refer to the figure legend and surrounding text.

Background: Iron deficiency (ID) is common among people with chronic kidney disease (CKD) and/or heart failure (HF). Despite the additional burden ID causes among people with CKD and HF, there is considerable uncertainty surrounding the best way to diagnose it and, subsequently, identify who is most likely to benefit from receiving iron therapy. Methods: This manuscript reports the markers and thresholds used in ID diagnosis, treatment, and management in the UK by nephrologists and cardiologists who manage people with chronic kidney disease or heart failure, as well as investigating future challenges and questions that remain unanswered. The research involved three stages: an online questionnaire, individual interviews, and a panel meeting, which discussed the findings from the first two stages. Results: The panel concluded that there is no robust definition of iron deficiency that can be applied to chronic kidney disease and heart failure. Existing methods of diagnosing iron deficiency come with various problems; a transferrin saturation of <20% is the most popular, but it is not regarded as a perfect solution. Transferrin saturation is also the most popular way of assessing the success of iron deficiency treatment. Clinicians generally do not vary treatment regimens based on severity or subgroups. There are large variations in monitoring and the ability to administer iron therapy in secondary care. Conclusions: There is a clear need to consolidate current approaches to diagnosing and treating iron deficiency in people with chronic kidney disease and/or heart failure. Simple markers and thresholds, and simple strategies to implement them are required.

Background Novel collagen-derived circulating peptides, such as endotrophin, have been proposed as biomarkers of myocardial fibrosis. Objectives We aimed to determine the effect of pirfenidone, an antifibrotic agent, on circulating levels of these peptides, and their association with cardiovascular magnetic resonance extracellular volume (ECV). Methods In the PIROUETTE (Pirfenidone in Patients with Heart Failure and Preserved Left Ventricular Ejection Fraction) trial, novel collagen-derived circulating peptides (PRO-C3, C3M, CTX-III, endotrophin, PRO-C6, and C6M) were measured at baseline and at prespecified time points in patients with ECV ≥27% randomized (n = 94) to pirfenidone or placebo. Baseline peptide levels were also measured in patients with ECV <27% who were not randomized (n = 13). Results Treatment with pirfenidone was associated with a significant reduction in log endotrophin (P = 0.034), with a treatment effect seen from 13 weeks. After multivariable adjustment there were significant albeit modest associations between change in myocardial ECV and change in log endotrophin (R2: 0.14; P = 0.031), and baseline ECV and baseline log endotrophin (R2: 0.30; P = 0.022). Pirfenidone had no effect on the levels of other collagen-derived circulating peptides, and there were no associations between their levels and change in myocardial ECV or baseline ECV. Conclusions In patients with heart failure with preserved ejection fraction, treatment with pirfenidone was associated with a sustained reduction in circulating levels of endotrophin from 13 weeks. Circulating endotrophin was also independently associated with both baseline myocardial ECV and change in myocardial ECV. Endotrophin shows high potential as a circulating biomarker reflective of myocardial fibrosis burden and sensitive to change in myocardial fibrosis over time.

AIMS:Population-wide, person-level, linked electronic health record data are increasingly used to estimate epidemiology, guide resource allocation, and identify events in clinical trials. The accuracy of data from NHS Digital (now part of NHS England) for identifying hospitalization for heart failure (HHF), a key HF standard, is not clear. This study aimed to evaluate the accuracy of NHS Digital data for identifying HHF. METHODS AND RESULTS:Patients experiencing at least one HHF, as determined by NHS Digital data, and age- and sex-matched patients not experiencing HHF, were identified from a prospective cohort study and underwent expert adjudication. Three code sets commonly used to identify HHF were applied to the data and compared with expert adjudication (I50: International Classification of Diseases-10 codes beginning I50; OIS: Clinical Commissioning Groups Outcomes Indicator Set; and NICOR: National Institute for Cardiovascular Outcomes Research, used as the basis for the National Heart Failure Audit in England and Wales). Five hundred four patients underwent expert adjudication, of which 10 (2%) were adjudicated to have experienced HHF. Specificity was high across all three code sets in the first diagnosis position {I50: 96.2% [95% confidence interval (CI) 94.1-97.7%]; NICOR: 93.3% [CI 90.8-95.4%]; OIS: 95.6% [CI 93.3-97.2%]} but decreased substantially as the number of diagnosis positions expanded. Sensitivity [40.0% (CI 12.2-73.8%)] and positive predictive value (PPV) [highest with I50: 17.4% (CI 8.1-33.6%)] were low in the first diagnosis position for all coding sets. PPV was higher for the National Heart Failure Audit criteria, albeit modestly [36.4% (CI 16.6-62.2%)]. CONCLUSIONS:NHS Digital data were not able to accurately identify HHF and should not be used in isolation for this purpose.

The mitochondrial ribosome (mitoribosome) synthesizes 13 protein subunits of the oxidative phosphorylation system encoded by the mitochondrial genome. The mitoribosome is composed of 12S rRNA, 16S rRNA, and 82 mitoribosomal proteins encoded by nuclear genes. To date, variants in 12 genes encoding mitoribosomal proteins are associated with rare monogenic disorders and frequently show combined oxidative phosphorylation deficiency. Here, we describe five unrelated individuals with bi-allelic variants in death-associated protein 3 (DAP3), a nuclear gene encoding mitoribosomal small subunit 29 (MRPS29), with variable clinical presentations ranging from Perrault syndrome (sensorineural hearing loss and ovarian insufficiency) to an early childhood neurometabolic phenotype. Assessment of respiratory-chain function and proteomic profiling of fibroblasts from affected individuals demonstrated reduced MRPS29 protein amounts and, consequently, decreased levels of additional protein components of the mitoribosomal small subunit, as well as an associated combined deficiency of complexes I and IV. Lentiviral transduction of fibroblasts from affected individuals with wild-type DAP3 cDNA increased DAP3 mRNA expression and partially rescued protein levels of MRPS7, MRPS9, and complex I and IV subunits, demonstrating the pathogenicity of the DAP3 variants. Protein modeling suggested that DAP3 disease-associated missense variants can impact ADP binding, and in vitro assays demonstrated that DAP3 variants can consequently reduce both intrinsic and extrinsic apoptotic sensitivity, DAP3 thermal stability, and DAP3 GTPase activity. Our study presents genetic and functional evidence that bi-allelic variants in DAP3 result in a multisystem disorder of combined oxidative phosphorylation deficiency with pleiotropic presentations, consistent with mitochondrial dysfunction.

BACKGROUND:Studies predating widespread COVID-19 vaccination identified patients with congenital heart disease (CHD) as a group at increased risk of severe outcomes from COVID-19. Here we evaluate the impact of vaccination on COVID-19 outcomes among patients with CHD. METHODS:We conducted a case-control study using linked English electronic health records (n=3 18 135). Patients with CHD were matched with controls by age, sex, ethnicity and GP practice. The 'prevaccination' cohort comprised unvaccinated patients with CHD and matched controls with first-recorded SARS-CoV-2 infection between 1 March and 8 December 2020 (7805 cases, 27 620 controls). The 'post-vaccination' cohort comprised vaccinated patients with CHD and matched controls with first-recorded SARS-CoV-2 infection between 1 March 2021 and 1 April 2022, at least 14 days after vaccination (57 550 cases, 225 160 controls). Odds of severe COVID-19 outcomes were compared using conditional logistic regression. We also compared the rate at which vaccine efficacy diminished, and the incidence of vaccine-associated complications. RESULTS:Compared with the prevaccination cohort, postvaccination patients with CHD exhibited markedly reduced rates of COVID-19-related hospitalisation (0.5% vs 15.8%) and mortality rates (0.5% vs 4.6%). Compared with vaccinated controls, vaccinated patients with CHD remained at increased risk of hospitalisation (0.5% vs 0.2%, adjusted OR 2.24 (1.88-2.65); p<0.001) and death (0.5% vs 0.3%, adjusted OR 1.81 (1.54-2.13); p<0.001). There was no evidence that vaccine efficacy declined faster in patients with CHD, or that patients with CHD experienced a larger increase in incidence of myocarditis, pericarditis or thrombotic events. CONCLUSION:We observed a lower absolute risk of hospitalisation and death from COVID-19 in CHD patients after vaccination. However, in vaccinated CHD patients, an elevated risk of severe outcomes persists compared with vaccinated people without CHD. These results emphasise the importance of vaccination in the CHD population, and of vigilance among care providers dealing with COVID-19 infection in CHD patients, even if fully vaccinated.

The mitoribosome synthesizes 13 protein subunits of the oxidative phosphorylation system encoded by the mitochondrial genome. The mitoribosome is composed of 12S rRNA, 16S rRNA and 82 mitoribosomal proteins encoded by nuclear genes. To date, variants in 12 genes encoding mitoribosomal proteins are associated with rare monogenic disorders, and frequently show combined oxidative phosphorylation deficiency. Here, we describe five unrelated individuals with biallelic variants in the DAP3 nuclear gene encoding mitoribosomal small subunit 29 (MRPS29), with variable clinical presentations ranging from Perrault syndrome (sensorineural hearing loss and ovarian insufficiency) to an early childhood neurometabolic phenotype. Assessment of respiratory chain function and proteomic profiling of fibroblasts from affected individuals demonstrated reduced MRPS29 protein levels, and consequently decreased levels of additional protein components of the mitoribosomal small subunit, associated with a combined complex I and IV deficiency. Lentiviral transduction of fibroblasts from affected individuals with wild-type DAP3 cDNA increased DAP3 mRNA expression, and partially rescued protein levels of MRPS7, MRPS9 and complex I and IV subunits, demonstrating the pathogenicity of the DAP3 variants. Protein modelling suggested that DAP3 disease-associated missense variants can impact ADP binding, and in vitro assays demonstrated DAP3 variants can consequently reduce both intrinsic and extrinsic apoptotic sensitivity, DAP3 thermal stability and DAP3 GTPase activity. Our study presents genetic and functional evidence that biallelic variants in DAP3 result in a multisystem disorder of combined oxidative phosphorylation deficiency with pleiotropic presentations, consistent with mitochondrial dysfunction.

Abstract Background Heart failure (HF) with preserved or mildly reduced ejection fraction includes a heterogenous group of patients. Reclassification into distinct phenogroups to enable targeted interventions is a priority. This study aimed to identify distinct phenogroups, and compare phenogroup characteristics and outcomes, from electronic health record data. Methods 2,187 patients admitted to five UK hospitals with a diagnosis of HF and a left ventricular ejection fraction ≥ 40% were identified from the NIHR Health Informatics Collaborative database. Partition-based, model-based, and density-based machine learning clustering techniques were applied. Cox Proportional Hazards and Fine-Gray competing risks models were used to compare outcomes (all-cause mortality and hospitalisation for HF) across phenogroups. Results Three phenogroups were identified: (1) Younger, predominantly female patients with high prevalence of cardiometabolic and coronary disease; (2) More frail patients, with higher rates of lung disease and atrial fibrillation; (3) Patients characterised by systemic inflammation and high rates of diabetes and renal dysfunction. Survival profiles were distinct, with an increasing risk of all-cause mortality from phenogroups 1 to 3 (p < 0.001). Phenogroup membership significantly improved survival prediction compared to conventional factors. Phenogroups were not predictive of hospitalisation for HF. Conclusions Applying unsupervised machine learning to routinely collected electronic health record data identified phenogroups with distinct clinical characteristics and unique survival profiles.

Background: Heart failure (HF) most commonly occurs in patients who have had a myocardial infarction (MI), but factors other than MI size may be deterministic. Fibrosis of myocardium remote from the MI is associated with adverse remodeling. We aimed to 1) investigate the association between remote myocardial fibrosis, measured using cardiovascular magnetic resonance (CMR) extracellular volume fraction (ECV), and HF and death following MI, 2) identify predictors of remote myocardial fibrosis in patients with evidence of MI and determine the relationship with infarct size. Methods: Multicenter prospective cohort study of 1199 consecutive patients undergoing CMR with evidence of MI on late gadolinium enhancement. Median follow-up was 1133 (895-1442) days. Cox proportional hazards modeling was used to identify factors predictive of the primary outcome, a composite of first hospitalization for HF (HHF) or all-cause mortality, post-CMR. Linear regression modeling was used to identify determinants of remote ECV. Results: Remote myocardial fibrosis was a strong predictor of primary outcome (chi(2): 15.6, hazard ratio [HR]: 1.07 per 1% increase in ECV, 95% confidence interval [CI]: 1.04-1.11, p < 0.001) and was separately predictive of both HHF and death. The strongest predictors of remote ECV were diabetes, sex, natriuretic peptides, and body mass index, but, despite extensive phenotyping, the adjusted model R-2 was only 0.283. The relationship between infarct size and remote fibrosis was very weak. Conclusion: Myocardial fibrosis, measured using CMR ECV, is a strong predictor of HHF and death in patients with evidence of MI. The mechanisms underlying remote myocardial fibrosis formation post-MI remain poorly understood, but factors other than infarct size appear to be important.

Aims Rare, deleterious genetic variants in FLT4 are associated with Tetralogy of Fallot (TOF), the most common cyanotic congenital heart disease. The distinct genetic variants in FLT4 are also an established cause of Milroy disease, the most prevalent form of primary hereditary lymphoedema. The phenotypic features of these two conditions are non-overlapping, implying pleiotropic cellular mechanisms during development.Methods and results In this study, we show that FLT4 variants identified in patients with TOF, when expressed in primary human endothelial cells, cause aggregation of FLT4 protein in the perinuclear endoplasmic reticulum, activating proteostatic and metabolic signalling, whereas lymphoedema-associated FLT4 variants and wild-type (WT) FLT4 do not. FLT4 TOF variants display characteristic gene expression profiles in key developmental signalling pathways, revealing a role for FLT4 in cardiogenesis distinct from its role in lymphatic development. Inhibition of proteostatic signalling abrogates these effects, identifying potential avenues for therapeutic intervention. Depletion of flt4 in zebrafish caused cardiac phenotypes of reduced heart size and altered heart looping. These phenotypes were rescued with coinjection of WT human FLT4 mRNA, but incompletely or not at all by mRNA harbouring FLT4 TOF variants.Conclusion Taken together, we identify a pathogenic mechanism for FLT4 variants predisposing to TOF that is distinct from the known dominant negative mechanism of Milroy-causative variants. FLT4 variants give rise to conditions of the two circulatory subdivisions of the vascular system via distinct developmental pleiotropic molecular mechanisms. Graphical Abstract The differential subcellular localization of wild-type FLT4 , Milroy disease (MD), or Tetralogy of Fallot (TOF) variant, the subsequent downstream effects, and the predicted/characterized molecular mechanism of pathogenesis. (A) Graphical representation of FLT4 pleiotropy in TOF and MD. (B) Schematic representation of the cellular mechanism explicating the conclusions in (A).

ObjectiveIdentification of patients at risk of adverse outcome from heart failure (HF) at an early stage is a priority. Growth differentiation factor (GDF)-15 has emerged as a potentially useful biomarker. This study sought to identify determinants of circulating GDF-15 and evaluate its prognostic value, in patients at risk of HF or with HF but before first hospitalisation.MethodsProspective, longitudinal cohort study of 2166 consecutive patients in stage A–C HF undergoing cardiovascular magnetic resonance and measurement of GDF-15. Multivariable linear regression investigated determinants of GDF-15. Cox proportional hazards modelling, Net Reclassification Improvement and decision curve analysis examined its incremental prognostic value. Primary outcome was a composite of first hospitalisation for HF or all-cause mortality. Median follow-up was 1093 (939–1231) days.ResultsMajor determinants of GDF-15 were age, diabetes and N-terminal pro-B-type natriuretic peptide, although despite extensive phenotyping, only around half of the variability of GDF-15 could be explained (R20.51). Log-transformed GDF-15 was the strongest predictor of outcome (HR 2.12, 95% CI 1.71 to 2.63) and resulted in a risk prediction model with higher predictive accuracy (continuous Net Reclassification Improvement 0.26; 95% CI 0.13 to 0.39) and with greater clinical net benefit across the entire range of threshold probabilities.ConclusionIn patients at risk of HF, or with HF but before first hospitalisation, GDF-15 provides unique information and is highly predictive of hospitalisation for HF or all-cause mortality, leading to more accurate risk stratification that can improve clinical decision making.Trial registration numberNCT02326324.

Objectives: Medication adherence in patients with heart failure with preserved ejection fraction is unclear. This study sought to evaluate treatment adherence in the Pirfenidone in Patients with Heart Failure and Preserved Left Ventricular Ejection Fraction (PIROUETTE) trial. Methods and Results: Adherence was evaluated through pill counts and diary cards. Univariable and multivariable regression models were used to assess the relationship between adherence and baseline characteristics. Instrumental variable regression was used to estimate the causal effect of pirfenidone treatment duration on myocardial fibrosis. Complete adherence data were available in 54 of 80 participants completing the trial. Mean adherence to study medication was 94.7% and 96.9% in the pirfenidone and placebo groups, respectively. Each additional day of treatment with pirfenidone resulted in a significant decrease in myocardial extracellular volume (-0.004%; 95% confidence interval:-0.007% to-0.001%; P = 0.007). Associations with adherence included older age, higher symptom burden, lower body weight, and smaller right ventricular size. Conclusion: Adherence to study medication in the PIROUETTE trial was very high among patients for whom complete adherence data were available. Importantly, each additional day of treatment reduced myocardial fibrosis. Potential predictors of adherence were identified. Implementation of improved methods for assessing adherence is required.

Objective To determine the magnitude of any excess risk of mortality and hospitalisation due to COVID-19 infection in patients with congenital heart disease (CHD) in the UK healthcare system.Methods Matched case–control study within the Clinical Practice Research Datalink study of anonymised general practice records in the National Health Service in England. Patients with CHD were stratified for disease severity according to the European Society of Cardiology guidelines. Presence of a positive COVID-19 test, hospitalisation with a diagnosis of COVID-19 and COVID-19-related mortality were compared in case and control groups.Results 86 441 patients with CHD and 335 839 controls were studied. Of patients with a positive COVID-19 test, patients with CHD were more likely than controls to be hospitalised (22.4% vs 14.5%; OR=1.77 (95% CI 1.60 to 1.96); p=2.11e−28) and suffer COVID-19-related death (6.1% vs 3.8%; OR=1.60 (95% CI 1.35 to 1.89); p=7.00e−08). The excess risk of COVID-19 hospitalisation and death rose with increasing physiological severity of CHD (presence of pulmonary vascular disease and/or cyanosis), rather than anatomical complexity.Conclusions In this study of the COVID-19 pandemic experience, using population health records in over 86000 patients with CHD in England, patients with CHD with COVID-19 were at around 50–75% higher risk of hospitalisation and mortality compared with matched controls with COVID-19. We provide the first primary care-derived estimates for COVID-19 hospitalisation and case-fatality rates in patients with CHD. Some factors predictive of worse COVID-19 outcome in general populations (such as non-white ethnic group), and other CHD-specific comorbidities (such as pulmonary hypertension), influenced outcomes among patients with CHD.

Supplementary Figure 1: Serum levels of AMA-MMAE in mice. Supplementary Figure 2: Correlation plot of tumor growth inhibition versus specific tumor uptake. Supplementary Table 1: Overview results. Supplementary Table 2: Tumor growth inhibition study of mice bearing OVCAR3-X2.1 cells comparing the efficacy of 5mg/kg and 20mg/kg doses

Congenital heart disease (CHD) is the most common birth defect affecting around 1% global live births. The aetiology of CHD is poorly understood: while a number genetic loci have already been identified, the majority of cases remain unexplained. Many CHD cases occur with additional abnormalities, or as part of a defined syndrome (eg. Noonan or CHARGE syndromes). The 100,000 Genomes Project conducted whole genome sequencing for patients with a range of rare diseases and cancers in partnership with the UK National Health Service. We analysed clinical and genetic data from the project in 2638 participants with CHD, including both primary CHD cases and secondary cases who have CHD as part of a syndromic presentation but were recruited under other disease categories. Both cohorts are primarily composed of patients with CHD accompanied by additional extra-cardiac abnormalities without a prior diagnosis of a defined syndrome. We found that families recruited as primary CHD cases were significantly less likely to have been classed as “solved cases” (indicating a pathogenic variant has been identified) than phenotypically similar secondary CHD cases (5.4% primary, 16.2% secondary; p = 6.78х -11 ). This is primarily due to differences in the gene lists used in analysis, with the majority of diagnoses in both groups due to genes not included in the CHD gene panel (83% primary and 97% secondary cases). Expanding standard CHD screening to include a wider range of syndromic CHD genes is likely to increase the diagnostic yield for the primary CHD cohort by more than two-fold. Copy number variants (CNVs) also contribute to CHD, especially in cases with additional abnormalities. CHD cases have a significantly higher burden of both deletions (p = 1.00х10 -5 ) and duplications (p = 0.009) than an ethnically-matched control cohort. However, only 7 of 2638 participants have CNVs in known CHD-causative regions such as the 22q11.2 or Williams-Beuren syndrome regions indicating novel CNVs are likely to contribute to a significant number of cases. Wider screening of syndromic CHD genes and novel copy number variants is likely significantly increase the diagnostic yield for CHD both within the 100,000 Genomes Project and in healthcare settings, and potentially yield novel CHD-associated loci.