Journal Article

Proteomic profiling identifies molecular subtypes and unveils mechanistic insights into clinical features of hypertrophic cardiomyopathy

Wang, Shuiyun, Zheng, Xinxin, Guo, Xinli, Nie, Changrong, Huang, Xiaohong, Song, Changpeng

2026

Overview

Background Hypertrophic cardiomyopathy (HCM) is the most common inherited heart disease, shows significant genetic and clinical heterogeneity, yet its molecular basis remains unclear. This study aims to uncover molecular insights behind HCM based on proteomic analysis. Methods We performed proteomic analysis on formalin-fixed paraffin-embedded septal tissue samples from 105 patients with obstructive HCM undergoing myectomy, including 35 with MYBPC3 and 35 with MYH7 mutations. The primary outcome was major adverse cardiovascular events (MACE), comprising all-cause mortality and other major cardiovascular events. Results We identified four molecular subtypes: 39 patients with subtype-I (S-I), 38 with S-II, 27 with S-III, and 1 with S-IV. During a median follow-up of 6.8 years, 28.6% of patients developed MACE. Among the subtypes, S-III exhibited the minimal fibrosis and the best clinical outcomes. S-II presented the most severe phenotype and poorest prognosis, characterized by activation of inflammatory and fibrotic pathways, along with downregulation of multiple metabolic processes. Compared to S-II, S-I displayed opposing pathway patterns and better outcomes, with a predominance of MYBPC3 mutation carriers. Beisides, we identified protein modules that were associated with genotypes and clinical features. MYH7-related modules were positively correlated with fibrosis and MACE, primarily enriched in inflammatory and fibrotic pathways. In contrast, MYBPC3-related modules were linked to better clinical outcomes, enriched in energy metabolism pathways. Conclusions This proteomic study revealed molecular mechanisms linking genotype, fibrosis and prognosis in HCM, and identified potential drivers of high-risk subtypes with severe phenotypes. These findings may guide future risk stratification and therapeutic target development. Graphical Abstract

• Publisher: BioMed Central,BioMed Central Ltd,Springer Nature B.V,BMC
• Subject: Adult / Analysis / Biomedical and Life Sciences / Biomedicine / Cardiac Myosins - genetics / Cardiomyopathy / Cardiomyopathy, Hypertrophic / Cardiomyopathy, Hypertrophic - classification / Cardiomyopathy, Hypertrophic - genetics / Cardiomyopathy, Hypertrophic - metabolism / Cardiomyopathy, Hypertrophic - pathology / Cardiovascular diseases / Care and treatment / Carrier Proteins - genetics / Chi-square test / Collagen / Diagnosis / Disease / Energy metabolism / Female / Fibrosis / Genetic aspects / Genetic variation / Genotype & phenotype / Genotypes / Heart diseases / Hospitals / Humans / Hypertrophic cardiomyopathy / Inflammation / Male / Medical bioinformatics / Medical prognosis / Medicine/Public Health / Middle Aged / Molecular mechanism / Molecular modelling / Mutation / Mutation - genetics / Myosin Binding Protein C / Myosin Heavy Chains - genetics / Patients / Peptides / Phenotype / Phenotypes / Prognosis / Protein expression / Proteins / Proteomics / Subtypes / Therapeutic targets / Variance analysis / Work stations