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

Abstract

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.

An Update on MYBPC3 Gene Mutation in Hypertrophic Cardiomyopathy

“…There appear to be potential biomarkers for severe phenotypes of MYBPC3-associated HCM. Multiple pathways, including acylcarnitine, histidine, lysine, purine, steroid hormone metabolism, and proteolysis are altered in these patients, which could lead to possible risk stratification methods in the future [ 87 ].…”

Molecular Mechanisms of Cardiac Development and Disease

“…Using direct-infusion high-resolution mass spectrometry, the group of Annette F. Baas performed a study to comprehensively compare metabolites among severely and mildly affected carriers of Hypertrophic Cardiomyopathy (HCM)-causing variants. They could associate several metabolic pathways, including histidine, lysine, acylcarnitine, purine and steroid hormone metabolism with cases of severe HCM, which might in the future give additional indications for the pathogenesis, prognostic, and therapeutic care of patients with HCM [16]. Francesca Di Lorenzo and colleagues propose to define variants in the Desmoplakin (DSP) gene as an own clinical entity in the case of arrhythmogenic cardiomyopathy (ACM) and dilated cardiomyopathy (DCM).…”