Multi-Omics Profiling of Hypertrophic Cardiomyopathy Reveals Altered Mechanisms in Mitochondrial Dynamics and...

Area of Science:

• Cardiovascular Research
• Genetics
• Molecular Biology

Background:

• Hypertrophic cardiomyopathy (HCM) is a common inherited heart muscle disease and a major cause of sudden cardiac death in young individuals.
• Existing genetic knowledge shows an imperfect link between mutations and clinical outcomes, indicating complex disease pathways.
• Understanding early molecular events is crucial for developing targeted therapies.

Purpose of the Study:

• To investigate the early molecular consequences of myosin heavy chain mutations in hypertrophic cardiomyopathy.
• To compare early cellular responses in engineered heart cells with late-stage disease manifestations in patient tissues.
• To identify novel molecular mechanisms driving HCM pathogenesis.

Main Methods:

• Integrated quantitative multi-omics analysis (proteomics, phosphoproteomics, metabolomics).
• Utilized engineered human induced pluripotent stem-cell-derived cardiomyocytes (hiPSC-CMs).
• Analyzed patient-derived myocardial tissue samples representing late-stage disease.

Main Results:

• Identified hundreds of differential molecular features, including proteins, phosphoproteins, and metabolites.
• Revealed early modulation of mitochondrial homeostasis in response to mutations.
• Uncovered stage-specific metabolic and excitation-coupling maladaptations.
• Observed protective cellular responses preceding contractile dysfunction.

Conclusions:

• This study provides novel insights into the early molecular events in hypertrophic cardiomyopathy pathogenesis.
• The findings highlight the role of mitochondrial homeostasis and metabolic adaptation in early disease stages.
• Understanding these initial responses may reveal new therapeutic targets for preventing disease progression.