TY - JOUR
T1 - Bioinformatics multivariate analysis determined a set of phase-specific biomarker candidates in a novel mouse model for viral myocarditis
AU - Omura, Seiichi
AU - Kawai, Eiichiro
AU - Sato, Fumitaka
AU - Martinez, Nicholas E.
AU - Chaitanya, Ganta V.
AU - Rollyson, Phoebe A.
AU - Cvek, Urska
AU - Trutschl, Marjan
AU - Alexander, J. Steven
AU - Tsunoda, Ikuo
N1 - Publisher Copyright:
© 2014 American Heart Association, Inc.
PY - 2014/8/1
Y1 - 2014/8/1
N2 - Background: Myocarditis is an inflammatory disease of the cardiac muscle and is mainly caused by viral infections. Viral myocarditis has been proposed to be divided into 3 phases: the acute viral phase, the subacute immune phase, and the chronic cardiac remodeling phase. Although individualized therapy should be applied depending on the phase, no clinical or experimental studies have found biomarkers that distinguish between the 3 phases. Theiler's murine encephalomyelitis virus belongs to the genus Cardiovirus and can cause myocarditis in susceptible mouse strains. Methods and Results: Using this novel model for viral myocarditis induced with Theiler's murine encephalomyelitis virus, we conducted multivariate analysis including echocardiography, serum troponin and viral RNA titration, and microarray to identify the biomarker candidates that can discriminate the 3 phases. Using C3H mice infected with Theiler's murine encephalomyelitis virus on 4, 7, and 60 days post infection, we conducted bioinformatics analyses, including principal component analysis and k-means clustering of microarray data, because our traditional cardiac and serum assays, including 2-way comparison of microarray data, did not lead to the identification of a single biomarker. Principal component analysis separated heart samples clearly between the groups of 4, 7, and 60 days post infection. Representative genes contributing to the separation were as follows: 4 and 7 days post infection, innate immunity-related genes, such as Irf7 and Cxcl9; 7 and 60 days post infection, acquired immunity-related genes, such as Cd3g and H2-Aa; and cardiac remodeling-related genes, such as Mmp12 and Gpnmb. Conclusions: Sets of molecules, not single molecules, identified by unsupervised principal component analysis, were found to be useful as phase-specific biomarkers.
AB - Background: Myocarditis is an inflammatory disease of the cardiac muscle and is mainly caused by viral infections. Viral myocarditis has been proposed to be divided into 3 phases: the acute viral phase, the subacute immune phase, and the chronic cardiac remodeling phase. Although individualized therapy should be applied depending on the phase, no clinical or experimental studies have found biomarkers that distinguish between the 3 phases. Theiler's murine encephalomyelitis virus belongs to the genus Cardiovirus and can cause myocarditis in susceptible mouse strains. Methods and Results: Using this novel model for viral myocarditis induced with Theiler's murine encephalomyelitis virus, we conducted multivariate analysis including echocardiography, serum troponin and viral RNA titration, and microarray to identify the biomarker candidates that can discriminate the 3 phases. Using C3H mice infected with Theiler's murine encephalomyelitis virus on 4, 7, and 60 days post infection, we conducted bioinformatics analyses, including principal component analysis and k-means clustering of microarray data, because our traditional cardiac and serum assays, including 2-way comparison of microarray data, did not lead to the identification of a single biomarker. Principal component analysis separated heart samples clearly between the groups of 4, 7, and 60 days post infection. Representative genes contributing to the separation were as follows: 4 and 7 days post infection, innate immunity-related genes, such as Irf7 and Cxcl9; 7 and 60 days post infection, acquired immunity-related genes, such as Cd3g and H2-Aa; and cardiac remodeling-related genes, such as Mmp12 and Gpnmb. Conclusions: Sets of molecules, not single molecules, identified by unsupervised principal component analysis, were found to be useful as phase-specific biomarkers.
KW - Computational biology
KW - Immunology
KW - Interferons
KW - Picornaviridae infections
KW - Systems biology
KW - T lymphocytes
KW - Transcriptome
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U2 - 10.1161/CIRCGENETICS.114.000505
DO - 10.1161/CIRCGENETICS.114.000505
M3 - Article
C2 - 25031303
AN - SCOPUS:84911367894
SN - 1942-325X
VL - 7
SP - 444
EP - 454
JO - Circulation: Cardiovascular Genetics
JF - Circulation: Cardiovascular Genetics
IS - 4
ER -