Age-related decline in contractile function of ventricular myofibrils from HCM patients carrying MYBPC3 mutations

Cardiac Myosin Binding Protein C gene (MYBPC3) is the most frequent target of sarcomeric protein mutations associated to Hypertrophic Cardiomyopathy (HCM). Since a few years we have been examining the functional impact of these mutations directly in the cardiac sarcomeres of HCM patients undergoing septal myectomy. We use the single myofibril technique (Belus et al. 2008) to investigate Ca2+-sensitivity, mechanics and kinetics of contraction and relaxation of myofibrils isolated from myectomy samples of patients of different ages (range 18–68 year) carrying different MYBPC3 mutations. Preparations, mounted in a force recording apparatus (15C), are Ca2+-activated (pCa 6.50–4.50) and fully relaxed (pCa 8) by rapid (\10 ms) solution switching. Ca2+-sensitivity of tension is always increased in MYBPC3 mutant myofibrils compared to controls. Maximal isometric tension is always reduced and full tension relaxation upon Ca2+ removal is often impaired in the myofibrils from MYBPC3 mutant patients of any age. The rate constant of active tension generation following maximal Ca2+ activation (kACT)—as well as the rate of tension redevelopment following mechanical perturbations (kTR)—are significantly faster in the myofibrils from young MYBPC3 mutant patients (\40 year) as compared to controls. At older ages ([40 year) kACT and kTR of the mutant myofibrils progressively decline to levels that are the same as the controls or below the controls. Consistently, on a large HCM cohort we found that patients harbouring MYBPC3 mutations show an age-related decline in left ventricular function and are more likely to develop heart failure compared to other HCM patient groups. Acknowledgement: EU STREP-Project BIG-HEART 241577; Telethon GGP07133.