Hypertrophic cardiomyopathy (HCM) is frequently caused by mutations in MYBPC3 
encoding cardiac myosin-binding protein C (cMyBP-C). The mechanisms leading from 
gene mutations to the HCM phenotype remain incompletely understood, partially 
because current mouse models of HCM do not faithfully reflect the human 
situation and early hypertrophy confounds the interpretation of functional 
alterations. The goal of this study was to evaluate whether myofilament Ca(2+) 
sensitization and diastolic dysfunction are associated or precede the 
development of left ventricular hypertrophy (LVH) in HCM. We evaluated the 
function of skinned and intact cardiac myocytes, as well as the intact heart in 
a recently developed Mybpc3-targeted knock-in mouse model carrying a point 
mutation frequently associated with HCM. Compared to wild-type, 10-week old 
homozygous knock-in mice exhibited i) higher myofilament Ca(2+) sensitivity in 
skinned ventricular trabeculae, ii) lower diastolic sarcomere length, and faster 
Ca(2+) transient decay in intact myocytes, and iii) LVH, reduced fractional 
shortening, lower E/A and E'/A', and higher E/E' ratios by echocardiography and 
Doppler analysis, suggesting systolic and diastolic dysfunction. In contrast, 
heterozygous knock-in mice, which mimic the human HCM situation, did not exhibit 
LVH or systolic dysfunction, but exhibited higher myofilament Ca(2+) 
sensitivity, faster Ca(2+) transient decay, and diastolic dysfunction. These 
data demonstrate that myofilament Ca(2+) sensitization and diastolic dysfunction 
are early phenotypic consequences of Mybpc3 mutations independent of LVH. The 
accelerated Ca(2+) transients point to compensatory mechanisms directed towards 
normalization of relaxation. We propose that HCM is a model for diastolic heart 
failure and this mouse model could be valuable in studying mechanisms and 
treatment modalities.