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Circ Cardiovasc Genet. 2014 Apr;7(2):132-143. doi: 10.1161/CIRCGENETICS.113.000324. Epub 2014 Feb 28.

Desensitization of myofilaments to Ca2+ as a therapeutic target for hypertrophic cardiomyopathy with mutations in thin filament proteins.

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Department of Physiology and Biophysics, Center for Cardiovascular Research, University of Illinois, Chicago, IL.
Department of Physiology and Department of Cell Biology, Federal University of Parana, Curitiba, Brazil.
Department of Physiology and Cell Biology, The Davis Heart and Lung Research Institute, The Ohio State University, Columbus, OH.
Division of Molecular Cardiovascular Biology, Department of Pediatrics, Cincinnati Children's Hospital Medical Center, Cincinnati.
Department of Molecular Genetics, Biochemistry and Microbiology, University of Cincinnati, College of Medicine.
Department of Medicine, Section of Cardiology, University of Illinois, Chicago, IL.
Contributed equally



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 Ca(2+) 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.


We used an HCM mouse model with an E180G mutation in α-tropomyosin (Tm180) that demonstrates increased myofilament Ca(2+) sensitivity, severe hypertrophy, and diastolic dysfunction. To test our hypothesis, we reduced myofilament Ca(2+) sensitivity in Tm180 mice by generating a double transgenic mouse line. We crossed Tm180 mice with mice expressing a pseudophosphorylated cardiac troponin I (S23D and S24D; TnI-PP). TnI-PP mice demonstrated a reduced myofilament Ca(2+) sensitivity compared with 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 double transgenic compared with their Tm180 littermates, which express wild-type cardiac troponin I. Hearts of double transgenic mice demonstrated no changes in expression of phospholamban and sarcoplasmic reticulum Ca(2+) ATPase, increased levels of phospholamban and troponin T phosphorylation, and reduced phosphorylation of TnI compared with Tm180 mice. Moreover, expression of TnI-PP in Tm180 hearts inhibited modifications in the activity of extracellular signal-regulated kinase and zinc finger-containing transcription factor GATA in Tm180 hearts.


Our data strongly indicate that reduction of myofilament sensitivity to Ca(2+) and associated correction of abnormal relaxation can delay or prevent development of HCM and should be considered as a therapeutic target for HCM.


cardiac remodeling; cardiomyopathies; cardiomyopathy, hypertrophic; therapeutics

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