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

Area of Science:

• Cardiology
• Proteomics
• Genomics

Background:

• Hypertrophic cardiomyopathy (HCM) is a complex genetic heart disease with varied clinical presentations.
• Current risk stratification models for HCM rely on clinical data and have limited predictive accuracy for major adverse cardiovascular events (MACE).
• Understanding the molecular underpinnings of HCM is crucial for identifying distinct disease subtypes and improving patient outcomes.

Purpose of the Study:

• To identify molecular subtypes of hypertrophic cardiomyopathy (HCM) using plasma proteomics.
• To investigate the longitudinal associations between these molecular subtypes and the risk of MACE.
• To elucidate the underlying pathobiological mechanisms of distinct HCM molecular subtypes.

Main Methods:

• Unsupervised machine learning applied to plasma proteomics data from 258 HCM patients.
• Prospective follow-up for a median of 2.8 years to track MACE (composite of arrhythmia, heart failure, stroke, sudden cardiac death).
• Time-to-event analysis and pathway analysis to identify differences and biological mechanisms among subtypes.

Main Results:

• Four distinct molecular subtypes of HCM were identified.
• Significant differences in MACE-free survival were observed among the subtypes (p=0.007).
• Molecular subtype D exhibited a 3.41-fold increased risk of MACE compared to the lowest-risk subtype (p=0.003), associated with upregulated Ras/MAPK, inflammation, and fibrosis pathways.

Conclusions:

• Plasma proteomics can delineate molecular subtypes of hypertrophic cardiomyopathy (HCM).
• Distinct molecular subtypes of HCM are associated with differential risks of major adverse cardiovascular events (MACE).
• Identification of a high-risk HCM subtype linked to specific molecular pathways provides insights into disease mechanisms and potential therapeutic targets.