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Untargeted Metabolomics Identifies Potential Hypertrophic Cardiomyopathy Biomarkers in Carriers of MYBPC3 Founder

Mark Jansen1,2, Maike Schuldt3, Beau O van Driel3

  • 1Department of Genetics, University Medical Centre Utrecht, Utrecht University, 3584CX Utrecht, The Netherlands.

International Journal of Molecular Sciences
|February 25, 2023
PubMed

Insights

Metabolite profiles in carriers of MYBPC3 variants are linked to hypertrophic cardiomyopathy (HCM) severity. This study identified specific metabolic pathways associated with severe HCM phenotypes, aiding potential risk stratification for this common genetic heart disease.

Area of Science:

  • Cardiovascular Genetics
  • Metabolomics
  • Molecular Cardiology

Background:

  • Hypertrophic cardiomyopathy (HCM) is the most common monogenic heart disease, frequently caused by MYBPC3 variants.
  • Disease severity in HCM exhibits significant variability and incomplete penetrance.
  • Prior research indicates metabolic alterations in patients with HCM.

Purpose of the Study:

  • To identify distinct metabolite profiles associated with severe phenotypes in carriers of MYBPC3 founder variants.
  • To explore the relationship between metabolic changes and disease severity in a genetically defined HCM cohort.
  • To investigate potential metabolic biomarkers for HCM severity.

Main Methods:

  • Direct-infusion high-resolution mass spectrometry was employed to analyze plasma samples.
  • A case-control study design compared 30 severe HCM phenotype carriers with 30 mild/no phenotype carriers (MYBPC3 founder variants).
  • Statistical analyses including sparse partial least squares discriminant analysis, XGBoost, and Lasso logistic regression were used to identify significant metabolite peaks.

Main Results:

  • 36 out of 42 identified mass spectrometry peaks were significantly associated with severe HCM (p < 0.05).
  • Three metabolite peaks showed strong association with severe HCM (p < 0.001).
  • Associated metabolites were clustered into pathways including acylcarnitine, histidine, lysine, purine, steroid hormone metabolism, and proteolysis.

Conclusions:

  • This study identified specific metabolite profiles associated with severe phenotypes in MYBPC3 founder variant carriers.
  • The findings suggest potential utility of these metabolites as biomarkers for HCM severity.
  • Further research is warranted to confirm the role of these biomarkers in HCM pathogenesis and risk stratification.

Keywords:
MYBPC3biomarkershypertrophic cardiomyopathymetabolomics

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