Improving care for children with congenital heart disease by cardiovascular biomarker profiling and advanced non-invasive cardiac imaging techniques.

Background: Congenital heart disease (CHD) is the most common organ anomaly in humans affecting approximately 1:125 newborns worldwide. Early diagnosis enables postnatal stabilisation and may improve outcomes, especially in critical CHD, in which the circulation is dependent on patency of the arterial duct. Detection of CHD in newborns remains incomplete and current screening programs do not aim to detect less critical but common CHD types, such as atrial septal defects (ASD). Blood-based biomarkers may not only improve early diagnosis in newborns with critical CHD, but also in children with other common types of CHD, such as ASD. Direct comparison of blood biomarkers and advanced non-invasive cardiac magnetic resonance (CMR) imaging before and after ASD treatment in children, should allow for improved assessment of the complex cardiovascular remodelling process.Aims: Develop dried blood spot (DBS) assays for amino-terminal prohormone of brain natriuretic peptide (NT-proBNP) and interleukin-1 receptor-like 1 (IL-1RL1) to detect primarily high-risk CHD lesions, in which cardiac surgery is needed during infancy. Compare IL-1RL1 and CMR findings in children with ASD to assess a possible link between blood biomarker levels and cardiac imaging results. Explore intracardiac kinetic energy (KE) levels in paediatric ASD before and after treatment, using this CHD lesion as a model of a right-sided volume loading condition, to evaluate KE during the remodelling process.Methods: Case-control study settings to assess DBS assay performance of NT-proBNP and IL-1RL1 in newborns with CHD to improve early diagnoses. Evaluate IL-1RL1 in paediatric ASD cases before and after treatment versus controls, with direct comparison of blood levels to CMR findings, including intraventricular KE levels.Results: The developed DBS NT-proBNP test compared well to standard venous blood assay (correlation r=0.93; Bland-Altman bias±SD: -0.02±0.16; LoA: -0.32 to 0.30). The novel IL-1RL1 assay worked well when comparing DBS to venous blood analyses (correlation r=0.83; Bland-Altman bias±SD:1.00±0.17; LoA0.67 to 1.33). NT-proBNP by DBS analysis alone could identify CHD cases well (ROC: AUC=0.87) Combined NT-proBNP and IL-1RL1 analyses showed improved screening results (ROC: AUC=0.95). IL-1RL1 in newborns with ASD detected cases reasonably well (ROC: AUC=0.77). Levels of KE in children with ASD correlated with volumetric changes of the right and left ventricle following ASD closure. IL-1RL1 decreased in children after ASD treatment from a median [IQR] of 38.9 [22.2-57.6] to 34.1 [23.7-46.4] ng/ml; (p=0.04). Blood concentrations of IL-1RL1 correlated with decreases in right ventricular stoke volumes (r=0.43) and right ventricular systolic peak KE levels on CMR (r=0.50).Conclusions: The novel DBS assays for NT-proBNP and IL-1RL1 improved early postnatal diagnoses of CHD in this retrospective study setting. In children with ASD, prospective evaluation by advanced non-invasive cardiac imaging, including CMR assessment, the volumetric and KE changes following ASD treatment could be linked to corresponding IL-1RL1 blood levels. Findings reflect previously unrecognized relationships between IL-1RL1 blood levels and cardiac imaging results.