Myosin Binding Protein-C Mutations responsible for Hypertrophic Cardiomyophaty impair relaxation in human cardiac myofibrils

Cardiac Myosin Binding Protein-C (cMyBP-C) gene (MYBPC3) and myosin heavy chain (MHC) gene (MYH7) mutations are the most frequent mutations responsible for hypertrophic cardiomyopathy (FHC). Using fast solution switching techniques and single cardiac myofibrils isolated from the left side of the human interventricular septum, (control donors vs. patients carrying MYBPC3 and MYH7 FHC mutations) we study the mechanical alterations associated to FHC mutations. We previously reported that in human cardiac myofibrils expressing either MYBPC3 or MYH7 FHC mutations, kinetics of the slow isometric phase of force relaxation (slow kREL) were accelerated. This suggests a faster cross bridge detachment under isometric conditions and a greater energy cost of tension generation which may be a common trait to MYBPC3 and MYH7 FHC mutations (Belus et al., Biophys. J., 2008 suppl 94 1461). Here we report that despite the acceleration of slow kREL, in 20–50% of the MYBPC3 mutant myofibrils (from different patients) i)relaxation upon Ca2? removal was incomplete and overall relaxation duration was longer ii)slack sarcomere length was shorter and resting stiffness at optimal overlap was higher compared to controls. Thus in myofibrils carrying MYBPC3 mutations, the formation of force generating acto-myosin complexes may be not fully inhibited at diastolic [Ca2?]. Lack of full inhibition of acto-myosin interaction during diastole and increased myofilament Ca2?-sensitivity may contribute to the diastolic dysfunction observed in FHC patients carrying MYBPC3 mutations. Supported by Telethon-GGP07133 and MiUR-PRIN06