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(Circulation. 2008;117:1820-1831.)
© 2008 American Heart Association, Inc.

Heart Failure

Severe Heart Failure and Early Mortality in a Double-Mutation Mouse Model of Familial Hypertrophic Cardiomyopathy

Tatiana Tsoutsman, PhD; Matthew Kelly, BMedSc; Dominic C.H. Ng, PhD; Ju-En Tan, BMedSc; Emily Tu, BSc; Lien Lam, BMedSc; Marie A. Bogoyevitch, PhD; Christine E. Seidman, MD; J.G. Seidman, PhD; Christopher Semsarian, MB, BS, PhD

From the Agnes Ginges Centre for Molecular Cardiology (T.T., M.K., J.-E.T., E.T., L.L., C.S.), Centenary Institute, Sydney, New South Wales, Australia; Central Clinical School (T.T., C.S.), University of Sydney, New South Wales, Australia; Department of Biochemistry and Molecular Biology (D.C.H.N., M.B.), Bio21 Institute, University of Melbourne, Victoria, Australia; Department of Genetics and Howard Hughes Medical Institute (C.E.S., J.G.S.), Harvard Medical School, Boston, Mass; Cardiovascular Division (C.E.S.), Brigham and Women’s Hospital, Boston, Mass; and Department of Cardiology (C.S.), Royal Prince Alfred Hospital, Sydney, New South Wales, Australia.

Correspondence to Associate Professor Christopher Semsarian, Agnes Ginges Centre for Molecular Cardiology, Centenary Institute, Locked Bag 6, Newtown, NSW 2042, Australia. E-mail c.semsarian{at}centenary.org.au

Received November 27, 2007; accepted January 16, 2008.

Background— Familial hypertrophic cardiomyopathy (FHC) is characterized by genetic and clinical heterogeneity. Five percent of FHC families have 2 FHC-causing mutations, which results in earlier disease onset, increased cardiac dysfunction, and a higher incidence of sudden death events. These observations suggest a relationship between the number of gene mutations and phenotype severity in FHC.

Methods and Results— We sought to develop, characterize, and investigate the pathogenic mechanisms in a double-mutant murine model of FHC. This model (designated TnI-203/MHC-403) was generated by crossbreeding mice with the Gly203Ser cardiac troponin I (TnI-203) and Arg403Gln -myosin heavy chain (MHC-403) FHC-causing mutations. The mortality rate in TnI-203/MHC-403 mice was 100% by age 21 days. At age 14 days, TnI-203/MHC-403 mice developed a significantly increased ratio of heart weight to body weight, marked interstitial myocardial fibrosis, and increased expression of atrial natriuretic factor and brain natriuretic peptide compared with nontransgenic, TnI-203, and MHC-403 littermates. By age 16 to 18 days, TnI-203/MHC-403 mice rapidly developed a severe dilated cardiomyopathy and heart failure, with inducibility of ventricular arrhythmias, which led to death by 21 days. Downregulation of mRNA levels of key regulators of Ca²⁺ homeostasis in TnI-203/MHC-403 mice was observed. Increased levels of phosphorylated STAT3 were observed in TnI-203/MHC-403 mice and corresponded with the onset of disease, which suggests a possible cardioprotective response.

Conclusions— TnI-203/MHC-403 double-mutant mice develop a severe cardiac phenotype characterized by heart failure and early death. The presence of 2 disease-causing mutations may predispose individuals to a greater risk of developing severe heart failure than human FHC caused by a single gene mutation.

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CLINICAL PERSPECTIVE

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Clinical Summaries
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