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Background <p>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.</p> Methods <p>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.</p> Results <p>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.</p> Conclusions <p>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.</p> Graphical Abstract <p></p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年5月11日

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

摘要

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