Metabolomic biomarkers and metabolic remodelling in genetically characterised hypertrophic cardiomyopathy: a systematic review.

INTRODUCTION

Hypertrophic cardiomyopathy (HCM) is the most common inherited cardiomyopathy and a major cause of heart failure, malignant arrhythmias and sudden cardiac death. Although pathogenic variants in sarcomeric genes such as MYBPC3, MYH7, TNNT2, and TNNI3 are well-recognised contributors to the disease, the mechanisms linking these mutations to the heterogeneous phenotypes remain poorly understood. Increasing evidence suggests that HCM is fundamentally associated with disturbances in myocardial energetics and metabolic remodelling.

OBJECTIVES

This systematic review aimed to synthesise metabolomic evidence from genetically characterised HCM cohorts, with three specific objectives: (1) to characterise the metabolic pathways dysregulated in HCM, (2) to determine whether distinct metabolic signatures are associated with specific sarcomeric gene variants and (3) to evaluate the diagnostic, prognostic, and therapeutic relevance of identified metabolite biomarkers in HCM management. By explicitly examining whether genotype-specific metabolomic signatures exist in the current literature, this review addresses a question of direct relevance to precision medicine approaches in HCM.

METHODS

A systematic search of PubMed, Scopus and Web of Science identified 14 eligible studies comprising 1511 participants.

RESULTS

Most studies employed liquid chromatography-mass spectrometry (LCMS) based metabolomics using plasma or myocardial tissue samples. Across studies, recurrent metabolic alterations were observed in pathways related to fatty acid oxidation, branched-chain amino acid (BCAA) metabolism, ketone body utilisation, tricarboxylic acid (TCA) cycle intermediates and lipid metabolism. Circulating acyl carnitines, amino acids, and eicosanoid metabolites were among the most frequently reported biomarkers associated with disease presence or severity. Myocardial tissue analyses demonstrated impaired mitochondrial energetics, reductions in high-energy phosphate metabolites, and shifts toward alternative metabolic substrates.

CONCLUSION

No distinct genotype-specific metabolic signature was identified across studies; the metabolic remodelling pattern reflected phenotypic severity rather than the causal variants. While metabolomics shows potential in improving disease characterisation and biomarker discovery, further longitudinal and externally validated studies are required before clinical translation.