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1 Molecular Genetics, Biochemistry and Microbiology, University of Cincinnati College of Medicine, Cincinnati, Ohio, United States
2 Medicine, University of Maryland, Baltimore, Maryland, United States
3 Institute of Molecular Pharmacology & Biophysicso, University of Cincinnati College of Medicine, Cincinnati, Ohio, United States
4 Pathology, University of Cincinnati College of Medicine, Cincinnati, Ohio, United States
5 Department of Physiology and Biophysics, University of Illinois, Chicago College of Medicine, Chicago, Illinois, United States
6 Dept of Physiology & Biophysics, University of Illinois at Chicago, Chicago, Illinois, United States
7 Medicine, University of Maryland, Baltimore, Maryland, United States; University of Maryland, 20 Penn Street, Baltimore, Maryland, 21201, United States
8 Molecular Genetics, Biochemistry, and Microbiology, University of Cincinnati College of Medicine, Cincinnati, Ohio, United States
* To whom correspondence should be addressed. E-mail: david.wieczorek{at}uc.edu.
Familial hypertrophic cardiomyopathy is a disease caused by mutations in contractile proteins of the sarcomere. Our laboratory developed a mouse model of FHC with a mutation in the thin filament protein 
-tropomyosin at amino acid 180 (glutamic acid 180 glycine). The hearts of these mice exhibit dramatic systolic and diastolic dysfunction, and their myofilaments demonstrate increased calcium sensitivity. The mice also develop severe cardiac hypertrophy with death ensuing by 6 months. In an attempt to normalize calcium sensitivity in the cardiomyofilaments of the hypertrophic mice, we generated a chimeric -/
-TM protein which decreases calcium sensitivity in transgenic mouse cardiac myofilaments. By mating mice from these two models together, we tested the hypothesis that an attenuation of myofilament calcium sensitivity would modulate the severe physiological and pathological consequences of the familial hypertrophic cardiomyopathy mutation. These double transgenic mice "rescue" the hypertrophic phenotype by exhibiting a normal morphology with no pathological abnormalities. Physiological analyses of these rescued mice show improved cardiac function and normal myofilament calcium sensitivity. These results demonstrate that alterations in calcium response by modification of contractile proteins can prevent the pathological and physiological effects of this disease.
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