Stochastic allelic expression as trigger for contractile imbalance in hypertrophic cardiomyopathy

Area of Science:

• Cardiovascular Genetics
• Molecular Cardiology
• Inherited Cardiac Diseases

Background:

• Hypertrophic cardiomyopathy (HCM) is the most common inherited cardiac disease, characterized by cardiomyocyte hypertrophy, disarray, and fibrosis.
• The precise pathomechanism linking various sarcomeric gene mutations to HCM remains incompletely understood.
• A proposed unifying mechanism involves contractile imbalance, stemming from unequal force generation among cardiomyocytes.

Purpose of the Study:

• To investigate the role of contractile imbalance in the development of HCM hallmarks.
• To explore the relationship between cardiomyocyte force generation variability and HCM pathogenesis.
• To examine the molecular underpinnings of gene expression leading to contractile imbalance in HCM.

Main Methods:

• Comparative analysis of force generation in individual cardiomyocytes from HCM patients and healthy controls at identical calcium concentrations.
• Assessment of cell-to-cell variability in mRNA fractions for the MYH7 gene (encoding β-myosin heavy chain).
• Review of molecular mechanisms potentially driving burst-like gene transcription and allelic imbalance.

Main Results:

• Cardiomyocytes from HCM patients exhibited significantly greater variability in force generation compared to controls.
• Evidence suggests burst-like transcription of the MYH7 gene, leading to cell-to-cell allelic imbalance in mRNA.
• This imbalance in mutant vs. wild-type mRNA is hypothesized to cause unequal protein fractions and contractile imbalance.

Conclusions:

• Heterogeneity in cardiomyocyte force generation is a key feature of HCM.
• Cell-to-cell allelic imbalance in MYH7 gene expression contributes to contractile imbalance.
• Understanding these molecular mechanisms is crucial for elucidating HCM pathogenesis and developing targeted therapies.