Identification of Heparan Sulfate in Dilated Cardiomyopathy by Integrated Bioinformatics Analysis

Area of Science:

• Cardiovascular Biology
• Molecular Medicine
• Biochemistry

Background:

• Heparan sulfate (HS) and its proteoglycans (HSPGs) are crucial for mammalian biological processes.
• Dilated cardiomyopathy (DCM) is a complex heart condition with significant unmet needs.
• Understanding the molecular underpinnings of DCM is vital for developing targeted therapies.

Purpose of the Study:

• To investigate the role of heparan sulfate (HS) in the pathogenesis of dilated cardiomyopathy (DCM).
• To explore the association of HSPGs with key pathological features of DCM, including immune activation and cardiac fibrosis.
• To establish a novel molecular classification of DCM patients based on HSPG expression.

Main Methods:

• Integrated analysis of multiple high-throughput transcriptomic datasets (RNA sequencing, microarrays, single-cell RNA sequencing) from DCM patient hearts.
• Bioinformatic approaches including differential expression analysis, pathway enrichment, and immunocyte infiltration analysis.
• Identification of molecular subtypes of DCM based on HSPG expression patterns.

Main Results:

• Most HSPGs were significantly upregulated in DCM hearts, correlating with immune activation, cardiac fibrosis, and heart failure.
• Syndecan 2 (SDC2) expression was strongly associated with collagen I and III in cardiac fibroblasts.
• The HS biosynthetic pathway was activated, while HS-degrading enzymes were downregulated in DCM.
• A novel classification identified three DCM molecular subtypes (C1, C2, C3), with C1 exhibiting more severe fibrosis and heart failure.

Conclusions:

• Heparan sulfate plays a significant role in immune activation, cardiac fibrosis, and heart failure progression in DCM.
• HSPG expression provides a basis for a novel molecular classification of DCM patients.
• This classification may aid in understanding disease heterogeneity and guiding personalized treatment strategies.