Key result
TnI-203/MHC-403 double-mutant FHC mice show 100% mortality by three weeks from severe DCM and HF.
Why the study?
Carriers of two FHC-causing mutations have earlier disease onset and increased sudden death, suggesting a link between mutation number and phenotype severity, but underlying pathogenic mechanisms require investigation.
A double-mutant mouse model of familial hypertrophic cardiomyopathy demonstrates that the presence of two disease-causing mutations leads to a severe cardiac phenotype, early heart failure, and 100% mortality by 21 days, mirroring the severe phenotype seen in human double-mutation carriers.
Double-mutant mice develop severe HF and early death; leaves open whether compound mutations worsen human FHC prognosis.
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.
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Tsoutsman et al. (2008) studied Familial hypertrophic cardiomyopathy. Double-mutation (TnI-203/MHC-403) vs. Nontransgenic, TnI-203, and MHC-403 littermates was evaluated on Mortality rate by age 21 days. The TnI-203/MHC-403 double-mutant mouse model of familial hypertrophic cardiomyopathy exhibited a 100% mortality rate by age 21 days due to severe dilated cardiomyopathy and heart failure.
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