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

Mark Jansen*, Maike Schuldt, Beau O. van Driel, Amand F. Schmidt, Imke Christiaans, Saskia N. van der Crabben, Yvonne M. Hoedemaekers, Dennis Dooijes, Jan D.H. Jongbloed, Ludolf G. Boven, Ronald H.Lekanne Deprez, Arthur A.M. Wilde, Judith J.M. Jans, Jolanda van der Velden, Rudolf A. de Boer, J. Peter van Tintelen, Folkert W. Asselbergs, Annette F. Baas

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

3 Citations (Scopus)


Hypertrophic cardiomyopathy (HCM) is the most prevalent monogenic heart disease, commonly caused by pathogenic MYBPC3 variants, and a significant cause of sudden cardiac death. Severity is highly variable, with incomplete penetrance among genotype-positive family members. Previous studies demonstrated metabolic changes in HCM. We aimed to identify metabolite profiles associated with disease severity in carriers of MYBPC3 founder variants using direct-infusion high-resolution mass spectrometry in plasma of 30 carriers with a severe phenotype (maximum wall thickness ≥20 mm, septal reduction therapy, congestive heart failure, left ventricular ejection fraction <50%, or malignant ventricular arrhythmia) and 30 age- and sex-matched carriers with no or a mild phenotype. Of the top 25 mass spectrometry peaks selected by sparse partial least squares discriminant analysis, XGBoost gradient boosted trees, and Lasso logistic regression (42 total), 36 associated with severe HCM at a p < 0.05, 20 at p < 0.01, and 3 at p < 0.001. These peaks could be clustered to several metabolic pathways, including acylcarnitine, histidine, lysine, purine and steroid hormone metabolism, and proteolysis. In conclusion, this exploratory case-control study identified metabolites associated with severe phenotypes in MYBPC3 founder variant carriers. Future studies should assess whether these biomarkers contribute to HCM pathogenesis and evaluate their contribution to risk stratification.

Original languageEnglish
Article number4031
JournalInternational Journal of Molecular Sciences
Issue number4
Publication statusPublished - Feb 2023
Externally publishedYes

Bibliographical note

Funding Information:
This research was funded by the Netherlands Cardiovascular Research Initiative: An initiative with the support of the Dutch Heart Foundation (CVON2014-40 DOSIS, CVON2015-12 e-Detect, CVON2018-30 PREDICT2, and CVON2020B005 DOUBLE-DOSE); Dutch Heart Foundation (Dekker 2015T041); the Dutch Research Council (NWO)-ZonMW (VICI 91818602); ZonMW and Heart Foundation for the translational research program (95105003 ENERGY); UCL Hospitals NIHR Biomedical Research Centre.

Publisher Copyright:
© 2023 by the authors.


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