Fig. 6.

Contractile imbalance hypothesis for MYH7-mutations. In heterozygous HCM-patients, both MYH7 alleles are expressed burst-like; they are switched on and off in an independent and stochastic manner (active mutant and wildtype alleles are indicated by black and white stars). In adult human myocardium, in 27% of nuclei, both alleles were found switched off (no stars, i.e., no active transcription sites in scheme) [82]. Burst-like expression leads to heterogeneous fractions of wildtype and mutant mRNA in neighboring cells (indicated by differently shaded cells). This cell-to-cell allelic mRNA imbalance translates into highly heterogeneous fractions of wildtype and mutant β-MyHC protein among the cells. Due to the effect of the mutations on β-MyHC biomechanical function, the heterogeneous fractions cause imbalance in force generation from cell to cell that disrupts the cardiac syncytium over time. Stronger cells will overstretch weaker cells. This will most likely induce myocyte disarray, fibrosis, and hypertrophy