Is fast cross-bridge detachment a common feature to MYH7 and MYBP3 FHC-associated mutations in human cardiac myofibrils?

The R403Q mutation in the b-myosin heavy chain gene (MYH7), responsible for familial hypertrophic cardiomyopathy (FHC), leads to significant acceleration of force activation (kACT and kTR) and relaxation (slow kREL and fast kREL) kinetics and a diminution of maximal isometric tension (P0) of isolated human ventricular myofibrils (Belus et al., Biophys. J., 2007(suppl) Plat842, 181a). We suggested that the mutation accelerates the apparent rate with which cross-bridges leave their force generating states. Again, using fast solution switching techniques, we report here on the functional behaviour of left ventricular myofibrils isolated from 3 additional FHC patients undergoing septal myectomy: two carrying mutations in MYH7 (R694C or R442C) and one carrying the Y340X mutation in the cardiac myosin binding protein C gene (MYBPC3). Those carrying MYH7 mutations (R403Q, R692C, R442C) showed qualitatively similar changes: acceleration of relaxation kinetics (>2 times), decreased P0, marked (R403Q and R442C) or mild (R692C) acceleration of force activation kinetics, and higher Ca2þ -sensitivity (ca. 0.3 pCa unit). In contrast, in the patient carrying the MYBPC3 mutation force activation kinetics are markedly slowed while P0 (lower) and relaxation kinetics (ca. 2 times faster) behaved like in the MYH7 mutations (Ca2þ -sensitivity is under investigation). This suggests that faster cross-bridge detachment under isometric conditions and greater energy cost of tension generation may be common features to FHC-associated mutations independently of the exact mutation and sarcomeric protein involved. Supported by Telethon-GGP07133 and MIUR-PRIN06