Metabolite Signature in the Carriers of Pathogenic Genetic Variants for Cardiomyopathy: A Population-Based METSIM Study

Abstract

Hypertrophic (HCM) and dilated (DCM) cardiomyopathies are among the leading causes of sudden cardiac death. We identified 38 pathogenic or likely pathogenic variant carriers for HCM in three sarcomere genes (MYH7, MYBPC3, TPMI) among 9.928 participants of the METSIM Study having whole exome sequencing data available. Eight of them had a clinical diagnosis of HCM. We also identified 20 pathogenic or likely pathogenic variant carriers for DCM in the TTN gene, and six of them had a clinical diagnosis of DCM. The aim of our study was to investigate the metabolite signature in the carriers of the pathogenic or likely pathogenic genetic variants for HCM and DCM, compared to age- and body-mass-index-matched controls. Our novel findings were that the carriers of pathogenic or likely pathogenic variants for HCM had significantly increased concentrations of bradykinin (des-arg 9), vanillactate, and dimethylglycine and decreased concentrations of polysaturated fatty acids (PUFAs) and lysophosphatidylcholines compared with the controls without HCM. Additionally, our novel findings were that the carriers of pathogenic or likely pathogenic variants for DCM had significantly decreased concentrations of 1,5-anhydrogluticol, histidine betaine, N-acetyltryptophan, and methylsuccinate and increased concentrations of trans-4-hydroxyproline compared to the controls without DCM. Our population-based study shows that the metabolite signature of the genetic variants for HCM and DCM includes several novel metabolic pathways not previously described.

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

“…To the best of our knowledge, our study is the first to comprehensively compare metabolites among severely and mildly affected carriers of HCM-causing variants while accounting for confounding from age and sex. Five previous studies assessed blood-based metabolites using metabolomics in HCM patients, each with methodological differences compared with our study [ 34 , 35 , 36 , 37 , 38 ]. These include comparisons to hospital [ 35 ] or general population controls [ 36 ], not matching on age [ 37 ] or sex [ 36 , 37 ], differences in the range of analysed metabolites [ 34 , 35 , 36 , 38 ], and differences in outcomes [ 34 , 35 , 36 , 37 , 38 ].…”