Contractile dysfunction irrespective of the mutant protein in human hypertrophic cardiomyopathy with normal systolic function

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 (MYBPC3mut; n=17), mutation negative HCM patients without an identified sarcomere mutation (HCMmn; 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 mutby 33±5%, and similar in HCMmn compared with donor. cMyBP-C phosphorylation in MYBPC3 mutwas similar to donor, whereas it was significantly lower in HCMmn. 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 mutand HCMmn, compared with donor (26.4±2.9, 28.0±3.7, and 37.2±2.3 kN/m2, respectively), and higher myofilament Ca 2+-sensitivity (EC50=2.5±0.2, 2.4±0.2, and 3.0±0.2 =mol/L, respectively). The sarcomere length-dependent increase in Ca 2+-sensitivity was significantly smaller in both patient groups compared with donor (δEC50: 0.46±0.04, 0.37±0.05, and 0.75±0.07 =mol/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.

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