title: Severe heart failure and early mortality in a double-mutation mouse model of familial hypertrophic cardiomyopathy.
abstract: 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.
  
  
  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.
authors: Agnes Ginges Centre for Molecular Cardiology, Centenary Institute, Locked Bag 6, Newtown, NSW 2042, Australia.
authors: Tatiana
authors: T
authors: Tsoutsman
authors: Matthew
authors: M
authors: Kelly
authors: Dominic C H
authors: DC
authors: Ng
authors: Ju-En
authors: JE
authors: Tan
authors: Emily
authors: E
authors: Tu
authors: Lien
authors: L
authors: Lam
authors: Marie A
authors: MA
authors: Bogoyevitch
authors: Christine E
authors: CE
authors: Seidman
authors: J G
authors: JG
authors: Seidman
authors: Christopher
authors: C
authors: Semsarian
mesh_terms: D000818:Animals; D020013:Calcium Signaling; D002311:Cardiomyopathy, Dilated / Q000235:genetics* / Q000473:pathology; D024741:Cardiomyopathy, Hypertrophic, Familial / Q000235:genetics* / Q000503:physiopathology; D004195:Disease Models, Animal; D018450:Disease Progression; D005260:Female; D006579:Heterozygote; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D009154:Mutation; D020125:Mutation, Missense; D019899:Paracrine Communication; D010641:Phenotype; D012084:Renin-Angiotensin System / Q000502:physiology; D050796:STAT3 Transcription Factor / Q000502:physiology; D015398:Signal Transduction; D019210:Troponin I / Q000235:genetics*; D024723:Ventricular Myosins / Q000235:genetics* / Q000502:physiology
chemical_list: D050796:STAT3 Transcription Factor; C494087:Stat3 protein, mouse; D019210:Troponin I; D024723:Ventricular Myosins