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Biomarkers and Proteomics in Sarcomeric Hypertrophic Cardiomyopathy in the Young-FGF-21 Highly Associated with Overt
Anna Wålinder Österberg1, Ingegerd Östman-Smith2, Henrik Green3
1Crown Princess Victoria Children's Hospital, Linköping University Hospital and Division of Pediatrics, Department of Biomedical and Clinical Sciences, Linköping University, SE-58183 Linköping, Sweden.
Insights
Biomarker differences in hypertrophic cardiomyopathy (HCM) patients reveal Fibroblast growth factor-21 (FGF-21) involvement in the RAS-MAPK pathway, crucial for cardiomyocyte hypertrophy, regardless of genetic background.
Area of Science:
- Cardiovascular Biology
- Genetics
- Biomarker Discovery
Background:
- Investigating biomarker differences between overt hypertrophic cardiomyopathy (HCM) and genotype-positive, phenotype-negative (G+P-) individuals can elucidate pathophysiological mechanisms.
- Focus on young HCM patients and G+P- individuals provides unique insights into early disease development.
Purpose of the Study:
- To identify distinct protein biomarker profiles in young HCM patients compared to G+P- individuals and controls.
- To explore the association of these biomarkers with HCM pathophysiology, particularly the RAS-MAPK pathway.
Main Methods:
- Prospective analysis of 29 HCM patients, 17 G+P- individuals, and matched controls.
- Utilized proximity extension assays to analyze 184 cardiovascular disease-associated proteins across biological pathways.
- Employed multivariate logistic regression and dichotomized protein values for statistical analysis.
Main Results:
- Overt HCM phenotype showed significantly higher odds ratios for Fibroblast growth factor-21 (FGF-21), P-selectin glycoprotein ligand-1 (PSGL-1), and Galectin-9 (Gal-9).
- G+P- individuals exhibited a notably raised angiopoietin-1 receptor (TIE2) and reduced metalloproteinase inhibitor 4 (TIMP4).
- FGF-21, linked to the RAS-MAPK pathway, was significantly associated with cardiomyocyte hypertrophy in HCM.
Conclusions:
- This study highlights FGF-21's upregulation in HCM, indicating RAS-MAPK pathway involvement irrespective of genetic background.
- Identified distinct biomarker profiles in overt HCM versus G+P- individuals, offering potential diagnostic or prognostic markers.
- The findings provide novel insights into the molecular mechanisms underlying HCM development and progression.
Abstract:
Background: Any difference in biomarkers between genotype-positive individuals with overt hypertrophic cardiomyopathy (HCM), and genotype-positive but phenotype-negative individuals (G+P-) in HCM-associated pathways might shed light on pathophysiological mechanisms. We studied this in young HCM patients. Methods: 29 HCM patients, 17 G+P--individuals, and age- and sex-matched controls were prospectively included. We analyzed 184 cardiovascular disease-associated proteins by two proximity extension assays, categorized into biological pathways, and analyzed with multivariate logistic regression analysis. Significant proteins were dichotomized into groups above/below median concentration in control group. Results: Dichotomized values of significant proteins showed high odds ratio (OR) in overt HCMphenotype for Fibroblast growth factor-21 (FGF-21) 10 (p = 0.001), P-selectin glycoprotein ligand-1 (PSGL-1) OR 8.6 (p = 0.005), and Galectin-9 (Gal-9) OR 5.91 (p = 0.004). For G+P-, however, angiopoietin-1 receptor (TIE2) was notably raised, OR 65.5 (p = 0.004), whereas metalloproteinase inhibitor 4 (TIMP4) involved in proteolysis, in contrast, had reduced OR 0.06 (p = 0.013). Conclusions: This study is one of the first in young HCM patients and G+P- individuals. We found significantly increased OR for HCM in FGF-21 involved in RAS-MAPK pathway, associated with cardiomyocyte hypertrophy. Upregulation of FGF-21 indicates involvement of the RAS-MAPK pathway in HCM regardless of genetic background, which is a novel finding.
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