Sarcomere mutations in MYBPC3 and MYH7 significantly increased the energetic cost of cardiac contraction and reduced myocardial external efficiency compared to controls.
Observational (n=68)
Do MYBPC3 and MYH7 mutations increase the energetic cost of contraction in hypertrophic cardiomyopathy compared to mutation-negative patients and healthy controls?
Sarcomere mutations in MYBPC3 and MYH7 perturb the energetic cost of cardiac contraction, suggesting early metabolic treatment may be beneficial, especially in MYH7 mutation carriers.
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 from 26 manifest HCM patients (11 MYBPC3mut, 9 MYH7mut, 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 (11)C-acetate positron emission tomography and cardiovascular magnetic resonance imaging. Tension cost (TC), i.e. ATPase activity during force development, was higher in MYBPC3mut and MYH7mut compared with HCMsmn at saturating Ca(2+). TC was also significantly higher in MYH7mut at submaximal, more physiological Ca(2+). 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.
Witjas‐Paalberends et al. (Fri,) conducted a observational in Hypertrophic cardiomyopathy (n=68). MYBPC3 and MYH7 mutations vs. Sarcomere mutation-negative HCM and healthy controls was evaluated on Energetic cost of contraction (tension cost in vitro and myocardial external efficiency in vivo). Sarcomere mutations in MYBPC3 and MYH7 significantly increased the energetic cost of cardiac contraction and reduced myocardial external efficiency compared to controls.