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Investigating the Pathogenesis of MYH7 Mutation Gly823Glu in Familial Hypertrophic Cardiomyopathy using a Mouse Model
Published on: August 8, 2022
Proteogenomics of Hypertrophic Cardiomyopathy Reveals Subtype-Specific Therapy
Ke Ma1,2, Jie Yang1,2, Hongchang Guo1
1Beijing Anzhen Hospital, Capital Medical University, China (K.M., J.Y., H.G., P.L., Z.D., Jing Zhang, C.Z., P.Y., C.H., S.Z., G.L., J.D., Yang Li, Yulin Li).
Insights
This study identified two molecular subtypes of hypertrophic cardiomyopathy (HCM) based on proteogenomics, revealing metabolic differences and enabling targeted therapies for severe HCM patients.
Area of Science:
- Cardiovascular Biology
- Genomics
- Proteomics
- Metabolomics
Background:
- Hypertrophic cardiomyopathy (HCM) is a complex genetic heart disease with variable patient outcomes.
- Current understanding of HCM mechanisms is limited, hindering effective risk stratification and treatment.
- This study addresses the need for molecular insights into HCM heterogeneity.
Purpose of the Study:
- To identify molecular subtypes of HCM using integrated proteogenomic analysis.
- To explore subtype-specific therapeutic strategies for improved patient outcomes.
- To elucidate the causal link between molecular pathways and HCM pathogenesis.
Main Methods:
- Integrated proteogenomic analysis of 132 HCM patient myocardial samples (whole-exome sequencing, RNA sequencing, proteomics).
- Unsupervised clustering to define HCM subtypes, validated in independent cohorts and cellular models.
- In silico drug screening and in vitro/in vivo validation of subtype-specific therapeutic interventions.
Main Results:
- Two proteome-based HCM subtypes identified: severe and mild, with distinct clinical characteristics and prognoses.
- Severe HCM subtype predominantly driven by impaired fatty acid metabolism and oxidative phosphorylation.
- Genetic evidence confirmed a causal link between reduced fatty acid oxidation and HCM; Baicalin showed therapeutic potential.
Conclusions:
- Integrated proteogenomics reveals significant metabolic heterogeneity in HCM.
- Identified molecular subtypes allow for improved risk stratification.
- Subtype-specific therapeutic strategies, like Baicalin for severe HCM, offer new treatment avenues.
Background:
Hypertrophic cardiomyopathy (HCM) is a heterogeneous disease with diverse prognosis. The underlying mechanisms remain unknown, resulting in limited risk stratification and therapeutic strategies. This study aimed to elucidate molecular subtypes of HCM through integrated proteogenomic analysis and explore subtype-specific therapeutic strategies.
Methods:
We conducted an integrated proteogenomic analysis of 132 patients with HCM using myocardial samples, incorporating whole-exome sequencing, RNA sequencing, and proteomics. Unsupervised clustering was used to identify HCM subtypes, which were validated in heart tissues and human induced pluripotent stem cell-derived cardiomyocytes from 2 independent HCM subsets. Subtype-specific signatures and pathways were explored, and their causal link with HCM pathogenesis was established by genetic evidence. A subtype-specific drug was screened using in silico drug prediction, followed by in vitro and in vivo therapeutic effect assessments.
Results:
Integrated multi-omics analysis identified 2 proteome-based molecular subtypes, severe and mild. We identified 550 subtype-signature proteins, and enrichment analysis based on which revealed that the reduction in fatty acid metabolism and oxidative phosphorylation pathways in HCM versus healthy controls was predominantly driven by the severe subtype, with more severe clinical characteristics and poorer prognosis compared with the mild subtype. Validation in independent cohorts confirmed the robustness of the proteomic subtypes and their association with clinical severity. Additionally, key proteins in fatty acid oxidation and oxidative phosphorylation exhibited consistent expression differences among healthy controls and 2 HCM subtypes. Furthermore, genetic evidence established a causal link between reduced fatty acid oxidation and HCM pathogenesis. Baicalin, identified as a fatty acid oxidation facilitator, improved metabolic and hypertrophic phenotypes in severe subtype human induced pluripotent stem cell-derived cardiomyocytes and Myh6R404Q/+ mice.
Conclusions:
Our analysis demonstrates the metabolic heterogeneity of HCM and enables the development of risk stratification and subtype-specific therapeutic strategies.
Registration:
URL: https://www.clinicaltrials.gov; Unique identifier: NCT03076580.
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