Proteomics profiling reveals a distinct high-risk molecular subtype of hypertrophic cardiomyopathy

Objective Hypertrophic cardiomyopathy (HCM) is a heterogeneous disease, likely encompassing several subtypes of disease with distinct biological mechanisms (ie, molecular subtypes). Current models based solely on clinical data have yielded limited accuracy in predicting the risk of major adverse cardiovascular events (MACE). Our aim in this study was to derive molecular subtypes in our multicentre prospective cohort of patients with HCM using proteomics profiling and to examine their longitudinal associations with MACE. Methods We applied unsupervised machine learning methods to plasma proteomics profiling data of 1681 proteins from 258 patients with HCM who were prospectively followed for a median of 2.8 years. The primary outcome was MACE, defined as a composite of arrhythmia, heart failure, stroke and sudden cardiac death. Results We identified four molecular subtypes of HCM. Time-to-event analysis revealed significant differences in MACE-free survival among the four molecular subtypes (p(logrank)=0.007). Compared with the reference group with the lowest risk of MACE (molecular subtype A), patients in molecular subtype D had a higher risk of subsequently developing MACE, with an HR of 3.41 (95% CI 1.54 to 7.55, p=0.003). Pathway analysis of proteins differentially regulated in molecular subtype D demonstrated an upregulation of the Ras/mitogen-activated protein kinase and associated pathways, as well as pathways related to inflammation and fibrosis (eg, transforming growth factor-beta pathway). Conclusions Our prospective plasma proteomics study not only exhibited the presence of HCM molecular subtypes but also identified pathobiological mechanisms associated with a distinct high-risk subtype of HCM.

Automated summary

This study used proteomics profiling to identify molecular subtypes of hypertrophic cardiomyopathy (HCM) and examined their associations with major adverse cardiovascular events (MACE) in a multicenter prospective cohort. Four molecular subtypes of HCM were identified, and a high-risk subtype (subtype D) was found to be associated with upregulation of pathways related to inflammation, fibrosis, and Ras/mitogen-activated protein kinase. This prospective plasma proteomics study not only identified HCM molecular subtypes but also revealed pathobiological mechanisms associated with a high-risk subtype of HCM.