Background Hypertrophic cardiomyopathy (HCM) is a common genetic disorder caused mainly by mutations in sarcomeric proteins and is characterized by maladaptive myocardial hypertrophy, diastolic heart failure, increased myofilament Ca2+ sensitivity and high susceptibility to sudden death. We tested the following hypothesis: correction of the increased myofilament sensitivity can delay or prevent the development of the HCM phenotype. Methods and Results We used an HCM mouse model with an E180G mutation in α-tropomyosin (Tm180) that demonstrates increased myofilament Ca2+ sensitivity, severe hypertrophy and diastolic dysfunction. To test our hypothesis, we reduced myofilament Ca2+ sensitivity in Tm180 mice by generating a double transgenic (DTG) mouse line. We crossed Tm180 mice with mice expressing a pseudo-phosphorylated cardiac troponin I (cTnI) (S23D and S24D; TnI-PP). TnI-PP mice demonstrated a reduced myofilament Ca2+ sensitivity compared to wild-type mice. The development of pathological hypertrophy did not occur in mice expressing both Tm180 and TnI-PP. Left ventricle performance was improved in DTG compared to their Tm180 littermates, which express wild-type cTnI. Hearts of DTG mice demonstrated no changes in expression of phospholamban (PLN) and Serca2a, increased levels of PLN and TnT phosphorylation, and reduced phosphorylation of TnI compared to Tm180 mice. Moreover, expression of TnI-PP in Tm180 hearts inhibited modifications in the activity of ERK1/2 and GATA-4 in Tm180 hearts. Conclusions Our data strongly indicate that reduction of myofilament sensitivity to Ca2+ and associated correction of abnormal relaxation can delay or prevent development of HCM and should be considered as a therapeutic target for HCM.

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