Aims Disease mechanisms regarding hypertrophic cardiomyopathy (HCM) are largely unknown and disease onset varies. Sarcomere mutations might induce energy depletion for which until now there is no direct evidence at sarcomere level in human HCM. This study investigated if mutations in genes encoding myosin-binding protein C (MYBPC3) and myosin heavy chain (MYH7) underlie changes in the energetic cost of contraction in the development of human HCM disease. Methods and results Energetic cost of contraction was studied in vitro by measurements of force development and ATPase activity in cardiac muscle strips from26 manifestHCMpatients (11 MYBPC3mut, 9MYH7mut, and 6 sarcomere mutation-negative,HCMsmn). In addition, in vivo, the ratio between external work (EW) and myocardial oxygen consumption (MVO2) to obtain myocardial external efficiency (MEE) was determined in 28 pre-hypertrophic mutation carriers (14 MYBPC3mut and 14 MYH7mut) and 14 healthy controls using [11C]-acetate positron emission tomography and cardiovascular magnetic resonance imaging.Tension cost (TC), i.e.ATPase activity during force development, was higher in MYBPC3mut andMYH7mut compared with HCMsmn at saturating [Ca 2++]. TC was also significantly higher in MYH7mut at submaximal, more physiological [Ca2++]. EW was significantly lower in both mutation carrier groups, while MVO2 did not differ. MEE was significantly lower in both mutation carrier groups compared with controls, showing the lowest efficiency in MYH7 mutation carriers. Conclusion We provide direct evidence that sarcomere mutations perturb the energetic cost of cardiac contraction. Gene-specific severity of cardiac abnormalities may underlie differences in disease onset and suggests that early initiation of metabolic treatment may be beneficial, in particular, in MYH7 mutation carriers.

Hypertrophic cardiomyopathy, Mutation carriers, Myocardial efficiency, Sarcomere function, Sarcomere mutations
dx.doi.org/10.1093/cvr/cvu127, hdl.handle.net/1765/63130
Cardiovascular Research
Department of Clinical Genetics

Witjas-Paalberends, E.R, Güçlü, A, Germans, T, Knaapen, P, Harms, H.J, Vermeer, A.M.C, … van der Velden, J. (2014). Gene-specific increase in the energetic cost of contraction in hypertrophic cardiomyopathy caused by thick filament mutations. Cardiovascular Research, 103(2), 248–257. doi:10.1093/cvr/cvu127