Hypocontractile sarcomeres with lower maximal force generating capacity were observed in both MYBPC3-mutated (26.4 kN/m2) and mutation-negative HCM patients (28.0 kN/m2) compared to donors (37.2 kN/m2).
Observational (n=40)
Absolute Event Rate: 26.4% vs 37.2%
Background— Hypertrophic cardiomyopathy (HCM), typically characterized by asymmetrical left ventricular hypertrophy, frequently is caused by mutations in sarcomeric proteins. We studied if changes in sarcomeric properties in HCM depend on the underlying protein mutation. Methods and Results— Comparisons were made between cardiac samples from patients carrying a MYBPC3 mutation (MYBPC3 mut ; n=17), mutation negative HCM patients without an identified sarcomere mutation (HCM mn ; n=11), and nonfailing donors (n=12). All patients had normal systolic function, but impaired diastolic function. Protein expression of myosin binding protein C (cMyBP-C) was significantly lower in MYBPC3 mut by 33±5%, and similar in HCM mn compared with donor. cMyBP-C phosphorylation in MYBPC3 mut was similar to donor, whereas it was significantly lower in HCM mn . Troponin I phosphorylation was lower in both patient groups compared with donor. Force measurements in single permeabilized cardiomyocytes demonstrated comparable sarcomeric dysfunction in both patient groups characterized by lower maximal force generating capacity in MYBPC3 mut and HCM mn, compared with donor (26.4±2.9, 28.0±3.7, and 37.2±2.3 kN/m 2 , respectively), and higher myofilament Ca 2+ -sensitivity (EC 50 =2.5±0.2, 2.4±0.2, and 3.0±0.2 μmol/L, respectively). The sarcomere length-dependent increase in Ca 2+ -sensitivity was significantly smaller in both patient groups compared with donor (ΔEC 50 : 0.46±0.04, 0.37±0.05, and 0.75±0.07 μmol/L, respectively). Protein kinase A treatment restored myofilament Ca 2+ -sensitivity and length-dependent activation in both patient groups to donor values. Conclusions— Changes in sarcomere function reflect the clinical HCM phenotype rather than the specific MYBPC3 mutation. Hypocontractile sarcomeres are a common deficit in human HCM with normal systolic left ventricular function and may contribute to HCM disease progression.
Dijk et al. (Sat,) conducted a observational in Hypertrophic cardiomyopathy (n=40). MYBPC3 mutation vs. Mutation-negative HCM and nonfailing donors was evaluated on Maximal force generating capacity in single permeabilized cardiomyocytes (kN/m2). Hypocontractile sarcomeres with lower maximal force generating capacity were observed in both MYBPC3-mutated (26.4 kN/m2) and mutation-negative HCM patients (28.0 kN/m2) compared to donors (37.2 kN/m2).