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Published on: August 8, 2022
Novel Multiplexed Plasma Biomarker Panel Has Diagnostic and Prognostic Potential in Children With Hypertrophic
Gabriella Captur1,2,3, Ivan Doykov4, Sheng-Chia Chung5
1UCL MRC Unit for Lifelong Health & Ageing, UCL, London, United Kingdom (G.C.).
Insights
New plasma proteomics panels accurately identify childhood hypertrophic cardiomyopathy (HCM) and predict sudden cardiac death risk. This 7-biomarker panel distinguishes HCM patients from healthy children, while a 4-biomarker panel identifies high-risk individuals.
Area of Science:
- Cardiovascular Proteomics
- Pediatric Cardiology
- Biomarker Discovery
Background:
- Hypertrophic cardiomyopathy (HCM) is clinically defined by pathological left ventricular hypertrophy.
- Previous research established plasma proteomics biomarkers for adult HCM severity and sudden cardiac death risk.
- The need exists to identify and validate biomarkers for childhood-onset HCM.
Purpose of the Study:
- To investigate the utility of adult HCM biomarkers in pediatric populations.
- To discover novel plasma proteomics biomarkers for childhood-onset HCM.
- To develop and validate predictive biomarker panels for pediatric HCM and associated risks.
Main Methods:
- Exploratory plasma proteomics identified 59 candidate biomarkers in children with HCM.
- These biomarkers were integrated into a targeted liquid chromatography-tandem/mass spectrometry assay.
- Machine learning techniques were employed to develop novel pediatric proteomic biomarker panels using prospective data from 148 children with HCM and 50 controls.
Main Results:
- A 7-biomarker panel, including 4 adult markers and 3 new ones (glycogen phosphorylase B, lipoprotein a, profilin 1), showed high diagnostic accuracy for pediatric HCM.
- This panel achieved an area under the curve of 1.0 in training and 0.82 in validation datasets.
- A separate 4-biomarker panel (apolipoprotein L1, complement 5b, immunoglobulin heavy constant epsilon, serum amyloid A4) identified children at high risk for adverse arrhythmic outcomes and mortality (HR, 2.04; P=0.044).
Conclusions:
- A 7-biomarker proteomics panel effectively distinguishes pediatric hypertrophic cardiomyopathy from healthy controls with high sensitivity and specificity.
- An additional 4-biomarker panel accurately identifies children at high risk for adverse arrhythmic events, including sudden cardiac death.
- These findings support the development of proteomic-based diagnostic and risk stratification tools for childhood HCM.
Background:
Hypertrophic cardiomyopathy (HCM) is defined clinically by pathological left ventricular hypertrophy. We have previously developed a plasma proteomics biomarker panel that correlates with clinical markers of disease severity and sudden cardiac death risk in adult patients with HCM. The aim of this study was to investigate the utility of adult biomarkers and perform new discoveries in proteomics for childhood-onset HCM.
Methods:
Fifty-nine protein biomarkers were identified from an exploratory plasma proteomics screen in children with HCM and augmented into our existing multiplexed targeted liquid chromatography-tandem/mass spectrometry-based assay. The association of these biomarkers with clinical phenotypes and outcomes was prospectively tested in plasma collected from 148 children with HCM and 50 healthy controls. Machine learning techniques were used to develop novel pediatric plasma proteomic biomarker panels.
Results:
Four previously identified adult HCM markers (aldolase fructose-bisphosphate A, complement C3a, talin-1, and thrombospondin 1) and 3 new markers (glycogen phosphorylase B, lipoprotein a and profilin 1) were elevated in pediatric HCM. Using supervised machine learning applied to training (n=137) and validation cohorts (n=61), this 7-biomarker panel differentiated HCM from healthy controls with an area under the curve of 1.0 in the training data set (sensitivity 100% [95% CI, 95-100]; specificity 100% [95% CI, 96-100]) and 0.82 in the validation data set (sensitivity 75% [95% CI, 59-86]; specificity 88% [95% CI, 75-94]). Reduced circulating levels of 4 other peptides (apolipoprotein L1, complement 5b, immunoglobulin heavy constant epsilon, and serum amyloid A4) found in children with high sudden cardiac death risk provided complete separation from the low and intermediate risk groups and predicted mortality and adverse arrhythmic outcomes (hazard ratio, 2.04 [95% CI, 1.0-4.2]; P=0.044).
Conclusions:
In children, a 7-biomarker proteomics panel can distinguish HCM from controls with high sensitivity and specificity, and another 4-biomarker panel identifies those at high risk of adverse arrhythmic outcomes, including sudden cardiac death.
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