Oral Presentation 2014 International Biophysics Congress

Hypertrophic cardiomyopathy (HCM) reflects the pathological phenotype associated with sarcomeric gene mutations. Affecting 1:500 individuals worldwide, HCM is the most common cause of sudden death in young people. Genotyping studies have identified a disease-causing mutation in ~70% of all HCM patients.

High myofilament Ca²⁺-sensitivity has been proposed as trigger of disease pathogenesis in HCM based on in vitro and transgenic mice studies. However, myofilament Ca²⁺-sensitivity depends on protein phosphorylation and muscle length and at present data in human are scarce. We investigated if high myofilament Ca²⁺-sensitivity and perturbed length-dependent activation is characteristic for human HCM with mutations in thick and thin filament proteins. Cardiac samples from HCM patients harboring mutations in genes encoding thick (MYH7, MYBPC3) and thin (TNNT2, TNNI3, TPM1) filament proteins were compared with sarcomere mutation-negative HCM (HCM_smn) and non-failing donors. Cardiomyocyte force measurements showed higher myofilament Ca²⁺-sensitivity in all HCMsamples and low phosphorylation of protein kinase A (PKA) sarcomere-targets compared to donors. After exogenous PKA treatment, myofilament Ca²⁺-sensitivity was either similar (MYBPC3_mut, TPM1_mut, HCM_smn), higher (MYH7_mut, TNNT2_mut) or even significantly lower (TNNI3_mut) compared to donors. Length-dependent activation was significantly smaller in all HCM than in donor samples. PKA treatment increased phosphorylation of PKA-targets in HCM myocardium and normalized length-dependent activation to donor values in HCM_smnand HCM with truncating MYBPC3 mutations, but not in HCM with missense mutations. Replacement of mutant by wild-type troponin in TNNT2_mut and TNNI3_mut corrected length-dependent activation to donor values.

High myofilament Ca²⁺-sensitivity is a common characteristic of human HCM and partly reflects hypophosphorylation of PKA-targets compared to non-failing donors. Length-dependent sarcomere activation is perturbed by missense mutations, possibly via post-translational modifications other than PKA-hypophosphorylation or altered protein-protein interactions, and represents a common pathomechanism in HCM.