Severe heart failure and early mortality in a double-mutation mouse model of familial hypertrophic cardiomyopathy

Article

关键词: CARDIAC TROPONIN-I;    TRANSGENIC RABBIT MODEL;    SIGNAL TRANSDUCER;    DILATED CARDIOMYOPATHY;    CLINICAL EXPRESSION;    ACTIVATOR;    GENE;    TRANSCRIPTION-3;    COMPOUND;    FIBROSIS;   

DOI  :  10.1161/CIRCULATIONAHA.107.755777

来源: SCIE

【 摘 要 】

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 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.

【 授权许可】

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