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

Tsoutsman, Tatiana, Kelly, Matthew, Ng, Dominic C. H., Tan, Ju-En, Tu, Emily, Lam, Lien, Bogoyevitch, Marie A., Seidman, Christine E., Seidman, J. G. and Semsarian, Christopher (2008) Severe heart failure and early mortality in a double-mutation mouse model of familial hypertrophic cardiomyopathy. Circulation, 117 14: 1820-1831. doi:10.1161/CIRCULATIONAHA.107.755777

Author Tsoutsman, Tatiana
Kelly, Matthew
Ng, Dominic C. H.
Tan, Ju-En
Tu, Emily
Lam, Lien
Bogoyevitch, Marie A.
Seidman, Christine E.
Seidman, J. G.
Semsarian, Christopher
Title Severe heart failure and early mortality in a double-mutation mouse model of familial hypertrophic cardiomyopathy
Journal name Circulation   Check publisher's open access policy
ISSN 0009-7322
Publication date 2008-04-01
Year available 2008
Sub-type Article (original research)
DOI 10.1161/CIRCULATIONAHA.107.755777
Open Access Status Not yet assessed
Volume 117
Issue 14
Start page 1820
End page 1831
Total pages 12
Place of publication Philadelphia, PA, United States
Publisher Lippincott Williams & Wilkins
Language eng
Formatted 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.

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 α-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 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.
Keyword Cardiomyopathy
Heart failure
Q-Index Code C1
Q-Index Status Provisional Code
Institutional Status Non-UQ

Document type: Journal Article
Sub-type: Article (original research)
Collection: School of Biomedical Sciences Publications
Version Filter Type
Citation counts: TR Web of Science Citation Count  Cited 50 times in Thomson Reuters Web of Science Article | Citations
Scopus Citation Count Cited 50 times in Scopus Article | Citations
Google Scholar Search Google Scholar
Created: Tue, 13 Jun 2017, 07:57:39 EST by Sarah Piper on behalf of Learning and Research Services (UQ Library)