Severe heart failure and early mortality in a double-mutation mouse model of familial hypertrophic cardiomyopathy.| Authors: | Tatiana Tsoutsman, Matthew Kelly, Dominic C H Ng, Ju-En Tan, Emily Tu, Lien Lam, Marie A Bogoyevitch, Christine E Seidman, J G Seidman, Christopher Semsarian | | Language: | Eng. | | Date: | 08-04-2008 | | Journal: | Circulation
(1524-4539)
| | Release: | Circulation. 2008 Apr;117(14):1820-31 | |
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Abstract:
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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 alpha-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 Ca(2+) 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.
| | Copyright: | Circulation
Agnes Ginges Centre for Molecular Cardiology, Centenary Institute, Locked Bag 6, Newtown, NSW 2042, Australia. | | Full text: | | | Terms: | Animals, Calcium Signaling, Cardiomyopathy, Dilated, Cardiomyopathy, Hypertrophic, Familial, Disease Models, Animal, Disease Progression, Female, Heterozygote, Humans, Male, Mice, Mice, Inbred C57BL, Mice, Mutant Strains, Mutation, Mutation, Missense, Paracrine Communication, Phenotype, Renin-Angiotensin System, STAT3 Transcription Factor, Signal Transduction, Troponin I, Ventricular Myosins | | |
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